Alternative titles; symbols
HGNC Approved Gene Symbol: APC
SNOMEDCT: 423471004, 60876000, 70921007, 72900001; ICD10CM: D13.91;
Cytogenetic location: 5q22.2 Genomic coordinates (GRCh38): 5:112,707,498-112,846,239 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q22.2 | Adenoma, periampullary, somatic | 175100 | 3 | |
| Adenomatous polyposis coli | 175100 | Autosomal dominant | 3 | |
| Brain tumor-polyposis syndrome 2 | 175100 | Autosomal dominant | 3 | |
| Colorectal cancer, somatic | 114500 | 3 | ||
| Desmoid disease, hereditary | 135290 | Autosomal dominant | 3 | |
| Gardner syndrome | 175100 | Autosomal dominant | 3 | |
| Gastric adenocarcinoma and proximal polyposis of the stomach | 619182 | Autosomal dominant | 3 | |
| Gastric cancer, somatic | 613659 | 3 | ||
| Hepatoblastoma, somatic | 114550 | 3 |
The APC gene encodes a multidomain protein that plays a major role in tumor suppression by antagonizing the WNT (see WNT1; 164820) signaling pathway. Inappropriate activation of this pathway through loss of APC function contributes to cancer progression, as in familial adenomatous polyposis (FAP; 175100). APC also has a role in cell migration, adhesion, chromosome segregation, spindle assembly, apoptosis, and neuronal differentiation (Hanson and Miller, 2005).
The APC protein is an integral part of the beta-catenin (CTNNB1; 116806) signaling pathway.
The APC gene was identified and cloned simultaneously and independently by 2 groups: the group of Bert Vogelstein in Baltimore, in collaboration with the group of Yusuke Nakamura in Tokyo (Kinzler et al., 1991; Nishisho et al., 1991), and the group of Ray White in Salt Lake City (Groden et al., 1991; Joslyn et al., 1991). The deduced 2,843-residue protein has a molecular mass of 311.8 kD. The protein sequence does not contain transmembrane regions or nuclear targeting signals, suggesting cytoplasmic localization.
Kinzler et al. (1991) identified several genes within a 5.5-Mb region of DNA linked to FAP. All were expressed in normal colonic mucosa: FER (176942), MCC (159350), SRP19 (182175), and TB2 (REEP5; 125265), in addition to the APC gene itself. The APC gene product was predicted to contain coiled-coil regions and was expressed in a wide variety of tissues.
Joslyn et al. (1991) identified 3 genes within small deleted regions on chromosome 5q12 found in 2 unrelated patients with FAP. One of these, termed DP2.5, was found by Groden et al. (1991) to be the APC gene. The other 2 genes identified by Joslyn et al. (1991) were SRP19 and DP1 (REEP5). Northern blot analysis by Groden et al. (1991) identified a 10-kb APC mRNA.
Hampton et al. (1992) isolated 2 overlapping YACs containing the MCC gene; one of the YACs also included the complete APC gene.
Lambertz and Ballhausen (1993) isolated cDNA clones representing transcripts expressed in human fetal brain and coding for the 5-prime end of the APC gene. Sequence analyses revealed an alternative 5-prime untranslated region comprising at least 103 bp. This finding suggested that 2 APC-specific promoter elements exist, giving rise to 2 different untranslated regions. Within the alternative UTR, Lambertz and Ballhausen (1993) identified 3 additional AUG codons, located 5-prime to the intrinsic APC initiation site. The authors suggested that these codons may be relevant for the translational regulation of APC gene expression.
Horii et al. (1993) noted that transcriptional initiation of APC occurs at 3 sites in 2 distinct nontranslated exons at the 5-prime end of the gene. Studies of transcripts from human colorectal tumor cell lines suggested the presence of mutations in the transcriptional control region. Horii et al. (1993) also detected at least 5 different forms of 5-prime noncoding sequences which were generated by alternative splicing. They stated that the splicing mechanism appeared to be regulated in a tissue-specific fashion, and 1 transcript, expressed exclusively in brain, contained an extra exon.
Groden et al. (1991) determined that the APC gene contains 15 exons.
Sulekova and Ballhausen (1995) identified a novel coding exon of the APC gene. To that point, the 54-bp exon (exon 10A) was the smallest coding exon in the gene, and was located 1.6-kb downstream from exon 10. It is alternatively spliced and inserted in-frame into mature transcripts; it gives an APC protein with an additional 18 amino acids. APC exon 10A flanking sequences were presented so that this exon could be included in mutation screening procedures.
Xia et al. (1995) described an alternatively spliced APC transcript which had not been reported previously. Within this transcript, they found an evolutionarily conserved but previously unidentified exon between the known exons 10 and 11. The exon contains a heptad repeat motif.
Karagianni et al. (2005) identified an alternatively spliced Apc transcript in mouse embryonic stem cells and colon tissue. The transcript contains an untranslated exon, which the authors designated exon N. Transcripts bearing exon N spliced to either exon 1 or exon 2 were detected in all mouse tissues examined. A promoter region within exon N has features of a housekeeping gene, including high average GC content and lack of CAAT and TATA boxes. Karagianni et al. (2005) mapped the promoter about 40 kb upstream of the initiating methionine, and transient transfection experiments showed strong promoter activity.
Gross (2014) mapped the APC gene to chromosome 5q22.2 based on an alignment of the APC sequence (GenBank AH009132) with the genomic sequence (GRCh38).
Hoshino et al. (1991) found that fragments of chromosome 5, including the region containing the APC gene, suppressed tumor activity when transferred into NIH-3T3 cells that had been transformed with Kirsten sarcoma virus.
Rubinfeld et al. (1993) and Su et al. (1993) found that APC associated with both beta-catenin (CTNNB1; 116806) and alpha-catenin (CTNNA1; 116805). Since both proteins bind to the cell adhesion molecule E-cadherin (192090), the results suggested that APC is involved in cell adhesion.
Peifer (1993) reviewed the role of the catenins in Drosophila and extrapolated the likely significance of the beta-catenin-APC interaction. One possibility is that the APC complex regulates transmission of the contact inhibition signal into the cell. This hypothesis would be consistent with the observation that APC mutations are associated with the development of hyperplasia, an early event in tumorigenesis. A second possibility is that the APC-catenin complex regulates adhesion. Although this idea is supported by evidence that loss of cadherin-mediated adhesion can contribute to metastasis, it would be less consistent with the evidence that APC acts early in tumorigenesis.
Smith et al. (1993) produced monoclonal and polyclonal antibodies to APC for characterizing the protein in normal and tumor cells. They found that 81% of colon tumor cell lines were totally devoid of the normal, full-length protein, whereas 40 cell lines derived from sporadic tumors of other organs had only full-length APC. Immunohistochemical analysis of APC in normal colonic mucosa demonstrated cytoplasmic staining with more intense staining in the basolateral margins of the epithelial cells. The staining was markedly increased in the upper portions of the crypts, suggesting an increased level of expression with maturation.
Miyashiro et al. (1995) discussed findings that suggested an important link between the role of APC in tumor initiation and the process of cellular adhesion. Immunohistochemical studies in normal mouse intestine suggested that a portion of the APC protein is localized in the lateral cytoplasm of intestinal epithelial cells and functions in cooperation with catenins, whereas the APC protein in microvilli and in the apical cytoplasm has other functions independent of catenins.
Matsumine et al. (1996) showed that the APC-beta-catenin complex binds to DLG (see 601014), the human homolog of the Drosophila discs large tumor suppressor protein. This interaction required the carboxyl-terminal region of APC and the homology repeat region of DLG. APC colocalized with DLG at the lateral cytoplasm in rat colon epithelial cells and at the synapse in cultured hippocampal neurons. Matsumine et al. (1996) suggested that the APC-DLG complex may participate in regulation of both cell cycle progression and neuronal function.
Rubinfeld et al. (1996) showed that when beta-catenin is present in excess, APC binds to a human homolog of 'Armadillo,' glycogen synthase kinase 3-beta (GSK3B; 605004), a component of the Wingless signaling pathway in Drosophila development.
Midgley et al. (1997) developed antisera to APC N- and C-terminal epitopes. They found that the APC protein was expressed in epithelial and mesenchymal cells in many tissues. In epithelium of bladder, small and large intestine, esophagus, stomach, and epidermis, APC expression was restricted to regions where cell replication has ceased and terminal differentiation is established. APC staining was often diffusely cytoplasmic; however, in surface cells there was accentuated expression in the subapical regions and along the lateral margins. Midgley et al. (1997) concluded that this distribution is compatible with APC function related to signaling at the adherens junction and indicates that APC plays a role in cells committed to terminal differentiation.
In mouse epithelial cells, Roose et al. (1999) found that TCF7 (189908) was one of the targets of the beta-catenin/TCF4 interaction. Roose et al. (1999) suggested that TCF7 may act as a feedback repressor of beta-catenin/TCF4 target genes, and thus may cooperate with APC to suppress malignant transformation of epithelial cells.
Using immunofluorescence microscopy, Neufeld and White (1997) found that full-length APC protein was present in both the nucleus and the cytoplasm of human mammary epithelial cells. The nuclear APC protein was concentrated in discrete subnuclear regions, including the nucleoli, whereas the cytoplasmic APC protein concentrated at the leading edge of migrating cells. Colocalization of APC protein with rRNA confirmed a nucleolar localization. Cell fractionation studies demonstrated full-length APC protein in both the membrane/cytoskeletal and the nuclear fractions. Neufeld et al. (2000) demonstrated that nuclear export of APC is mediated by 2 intrinsic, leucine-rich, nuclear export signals (NESs) located near the amino terminus. Each NES was able to induce the nuclear export of a fused carrier protein. Mutation of both APC NESs resulted in the nuclear accumulation of the full-length APC protein of approximately 320 kD, further establishing that the 2 intrinsic APC NESs are necessary for APC protein nuclear export. Moreover, endogenous APC accumulated in the nucleus of cells treated with the Crm1-specific nuclear export inhibitor leptomycin B. Together, these data indicated that APC is a nucleocytoplasmic shuttle protein whose predominantly cytoplasmic localization requires NES function, and suggested that APC may be important for signaling between the nuclear and cytoplasmic compartments of epithelial cells.
Kawasaki et al. (2000) cloned a gene, ASEF (605216), whose protein product was shown to directly interact with APC. ASEF immunoprecipitated with beta-catenin; however, ASEF and beta-catenin did not interact directly, suggesting that ASEF, APC, and beta-catenin are found in the same complex in vivo. Kawasaki et al. (2000) suggested that the APC-ASEF complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function.
Kaplan et al. (2001) showed that, during mitosis, wildtype APC localized to the ends of microtubules embedded in kinetochores and formed a complex with the checkpoint proteins Bub1 (602452) and Bub3 (603719). In vitro, APC was a high-affinity substrate for Bub kinases. Cells carrying a truncated APC gene were defective in chromosome segregation. Kaplan et al. (2001) concluded that there is a role for APC in kinetochore-microtubule attachment, and suggested that truncations in APC that eliminate microtubule binding may contribute to chromosomal instability in cancer cells.
By immunoprecipitation and pull-down assays using cells from FAP patients, cells from nonfamilial colorectal carcinoma patients, and normal human fetal lung fibroblasts, Homma et al. (2002) found that APC associated with the alpha (CSNK2A1; 115440) and beta (CSNK2B; 115441) subunits of casein kinase-2 (CK2). APC preferentially interacted with the tetrameric CK2 holoenzyme. In synchronized cells, association of APC with CK2 was cell cycle dependent. Full-length APC inhibited CK2 activity in vitro, and mutation analysis localized the inhibitory region to the C terminus of APC, between residues 2086 and 2394.
In a cell migration assay using primary rat astrocytes, Etienne-Manneville and Hall (2003) demonstrated that PAR6-PKC-zeta (176982) interacted with and regulated GSK3-beta to promote polarization of the centrosome and to control the direction of cell protrusion. CDC42 (116952)-dependent phosphorylation of GSK3-beta occurred specifically at the leading edge of migrating cells, and induced the interaction of APC protein with the plus ends of microtubules. The association of APC with microtubules was essential for cell polarization.
Yamashita et al. (2003) found that dividing Drosophila male germline stem cells used intracellular mechanisms involving centrosome function and cortically localized APC protein to orient mitotic spindles perpendicular to the niche, ensuring a reliably asymmetric outcome in which 1 daughter cell remains in the niche and self-renews stem cell identity, whereas the other, displaced away, initiates differentiation.
In cultured murine myocytes, Wang et al. (2003) found that agrin (103320)-induced acetylcholine receptor (AChR) postsynaptic aggregation required APC, which was found to colocalize and bind specifically to the AChR beta subunit (100710). The interaction occurred downstream of MuSK (601296) activation. Wang et al. (2003) suggested that a direct interaction between APC and the AChR beta subunit may link AChR to the cytoskeleton, helping to localize the receptors to the neuromuscular junction.
Using microarray and RT-PCR analyses, Jette et al. (2004) found that expression of 2 retinoid biosynthesis genes, RDH5 (601617) and RDHL (DHRS9; 612131), was reduced in colon adenomas and carcinomas compared with normal controls. Reintroduction of wildtype APC into an APC-deficient colon carcinoma cell line increased expression of RDHL without affecting RDH5. Induction of RDHL by APC appeared to depend on the presence of CDX2 (600297).
Choi et al. (2004) found that APC was downregulated by the ubiquitin-proteasome pathway in human 293T cells and that Wnt signaling inhibited this process. APC was ubiquitinated directly, and axin (AXIN1; 603816), which is present in the same protein complex as APC, facilitated APC downregulation. Furthermore, Choi et al. (2004) found that treatment of human 293T cells with WNT3A (606359) led to accumulation of APC and beta-catenin in nuclear lysates, providing support for the hypothesis that APC has a role in shuttling beta-catenin in and out of the nucleus.
Watanabe et al. (2004) found that monkey Iqgap1 (603379) and Apc interacted directly via the armadillo repeats of Apc and the C terminus of Iqgap1. Clip170 (179838) also immunoprecipitated with Apc and Iqgap1. Apc and Iqgap1 localized interdependently to the leading edge in migrating Vero cells, and transfection of cells with constitutively active human IQGAP1 provided accumulation sites with APC in a manner dependent on actin filaments. Watanabe et al. (2004) concluded that RAC1 (602048) and CDC42 recruit the IQGAP1/APC complex and that IQGAP1 links APC to actin filaments for cell polarization and directional migration.
By fractionating human and canine cell lysates over glycerol gradients, Penman et al. (2005) identified 2 distinct soluble protein pools containing APC. One of these pools represented fully assembled beta-catenin-targeting complexes. The second pool contained at least 2 different forms of APC: APC that was bound to partially assembled beta-catenin-targeting complexes and APC that could bind microtubules. Formation of fully assembled beta-catenin-targeting complexes was reduced by inhibitors of GSK3B. Highly elevated levels of beta-catenin in tumor cells correlated with decreased ability of endogenous APC to bind microtubules. Furthermore, APC lacking the direct microtubule-binding site was more effective at downregulating beta-catenin. Penman et al. (2005) concluded that interaction of APC with microtubules and with the beta-catenin-targeting complex are mutually exclusive.
By examining degradation of beta-catenin in human colon cancer cell lines with different APC truncations, Yang et al. (2006) determined that APC regulates beta-catenin phosphorylation and ubiquitination by distinct domains and by separate molecular mechanisms.
Migrating fibroblasts polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. Mili et al. (2008) used a fractionation scheme combined with microarrays to analyze protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. Mili et al. (2008) found that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3-prime untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the APC tumor suppressor and FMRP (309550). APC is required for the accumulation of transcripts in protrusions. Mili et al. (2008) concluded that their results suggested a new type of RNA anchoring mechanism as well as an unanticipated function for APC in localizing RNAs.
Tran et al. (2013) found that mouse Hectd1 (618649) colocalized and associated with Apc (611731) in a striatin (STRN; 614765)-dependent manner and modified Apc with lys63-linked polyubiquitin. Ubiquitin modification of Apc negatively regulated Apc accumulation at cortical protrusions and facilitated Apc interaction with Axin, thereby negatively impacting Wnt3a-induced stabilization and transcription of beta-catenin.
APC Gene Function in Disease
Unlike some other tumor suppressor genes, loss or mutation in the wildtype gene is not essential to the development of intestinal polyps (Fearon and Vogelstein, 1990). In a review, Kinzler and Vogelstein (1996) noted that the APC gene serves as a gatekeeper in colonic epithelial cells. The wildtype APC allele is lost in a great majority of colorectal tumors of both sporadic and FAP patients, consistent with the Knudson 2-hit model.
Powell et al. (1992) presented evidence that APC mutations occur early during colorectal tumorigenesis. Sequence analysis of 41 colorectal tumors revealed that most carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Mutations of the APC gene were found in the earliest tumors that could be analyzed, including adenomas as small as 0.5 cm in diameter, and the frequency of such mutations remained constant as tumors progressed from benign to malignant stages. This finding provided support for the multistage process of colorectal carcinogenesis with the APC gene at or near the initial step (Fearon and Vogelstein, 1990).
Fearon (1997) reviewed more than 20 different hereditary cancer syndromes that had been defined and attributed to specific germline mutations in various inherited cancer genes. A useful diagram illustrated how APC protein regulates beta-catenin levels in normal cells, and how mutations in APC or CTNNB1 in cancer cell genes deregulate cell growth via TCF4.
He et al. (1998) identified the c-myc (190080) oncogene as a target gene in the beta-catenin signaling pathway. Expression of MYC was shown to be repressed by wildtype APC and activated by beta-catenin, and these effects were mediated through TCF4 binding sites in the MYC promoter.
FAP is associated with an increased risk of developing papillary thyroid carcinomas (see 188550). A significant fraction of sporadic human papillary thyroid carcinomas have RET protooncogene rearrangements that generate chimeric transforming oncogenes designated RET/PTC (see RET; 164761). Cetta et al. (1998) found RET/PTC1 oncogene activation in 2 of 3 papillary carcinomas from an FAP kindred, and in the papillary carcinoma of a second FAP kindred. These findings showed that loss of function of APC coexists with gain of function of RET in some papillary thyroid carcinomas, suggesting that RET/PTC1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.
Soravia et al. (1999) described 2 FAP kindreds with thyroid cancer and different germline APC mutations (611731.0038 and 611731.0039, respectively). In 3 FAP patients, RET/PTC1 and RET/PTC3 were expressed in thyroid cancers; no positivity was observed for RET/PTC2. The findings suggested that loss of APC function and gain of RET/PTC function is an early event in FAP-associated thyroid tumorigenesis.
Lamlum et al. (1999) assembled evidence that APC mutations may not result in simple loss of protein function. They found that FAP patients with germline APC mutations within a small region (codons 1194 to 1392 at most) showed mainly allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tended to occur by truncating mutations in the mutation cluster region. These results indicated that different APC mutations provide cells with different selective advantages, with mutations close to codon 1300 providing the greatest advantage. Allelic loss was selected strongly in cells with 1 mutation near codon 1300. A different germline-somatic APC mutation association existed in FAP desmoids. Lamlum et al. (1999) concluded that APC is not, therefore, a classic tumor suppressor. Their findings indicated a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher, and more tumors grow.
Dihlmann et al. (1999) provided experimental evidence for a dominant-negative effect of APC gene products associated with severe polyposis. Wildtype APC activity in beta-catenin/TCF-mediated transcription was strongly inhibited by a mutant APC that is truncated at codon 1309 (611731.0023). In contrast, mutant APC gene products that are associated with attenuated polyposis, such as those involving codon 386 or 1465 (611731.0019), interfered only weakly with wildtype APC activity. These results suggested a molecular explanation for the genotype-phenotype correlation in FAP patients and supported the idea that colorectal tumor growth might be, in part, driven by selection for a mutation in the 'mutation cluster region' (MCR).
Lamlum et al. (1999) noted that APC seems to act as a tumor-suppressor gene in a 'nonclassical' fashion: the site of the germline mutation determines the type of 'second hit' in FAP tumors, and simple protein inactivation is selected weakly, if at all. In a screening of 210 colorectal adenomas from 35 FAP patients, Lamlum et al. (1999) found that patients with germline APC mutations around codon 1300 tended to acquire their second hit by allelic loss and had more severe disease. Other FAP patients tended to acquire their second hit by a truncating mutation in the MCR region of the APC gene.
Of 40 colorectal cancer cell lines, Rowan et al. (2000) found that 32 (83%) showed evidence of APC mutation and/or allelic loss. The authors identified several APC mutations and found a hotspot for somatic mutation in sporadic colorectal tumors at codon 1554. The results suggested that APC mutations occur in most colorectal cancers. When combined with previously published data, their results showed that there is interdependence of the 2 hits at APC in sporadic colorectal tumors as well as in FAP. APC mutations in the MCR, especially those close to codon 1300, were associated with allelic loss, whereas tumors with mutations outside this region tended to harbor truncating mutations. The causes of this phenomenon were thought to be selection for retained N-terminal and lost C-terminal APC functions, effects on beta-catenin levels, and APC protein stability.
Rosin-Arbesfeld et al. (2000) showed that APC contains highly conserved nuclear export signals 3-prime adjacent to the mutation cluster region that enable it to exit from the nucleus. Mutant APC in cancer cells lost this ability, ultimately resulting in the nuclear accumulation of beta-catenin. The findings suggested that the ability of APC to exit from the nucleus is critical for its tumor suppressor function.
In 2 families from Singapore with FAP, Cao et al. (2000) identified 2 deletions in the APC gene at exons 11 and 14, respectively. By mapping the precise breakpoints, Cao et al. (2001) confirmed that these deletions encompassed about 2 kb and 6 kb of the genomic regions encompassing exons 11 and 14, respectively. Detailed sequence analysis suggested that the 2-kb exon 11 deletion was most likely generated by a topoisomerase-I (TOP1; 126420)-mediated nonhomologous recombination and the 6-kb exon 14 deletion by an Alu-Alu homologous recombination. In the case of the first deletion, both 5-prime and 3-prime breakpoints had 2 topoisomerase I recognition sites and runs of pyrimidines within the 10-bp sequences in their vicinity. This was thought to be the first report of a topoisomerase-I-mediated germline mutation in a tumor suppressor gene. Both deletions resulted in truncated APC proteins missing the beta-catenin and axin-binding domains, resulting in severe polyposis and cancer.
Fearnhead et al. (2001) reviewed understanding of how mutations in the APC gene translate into changes at the protein level, which in turn contribute to the role of APC in tumorigenesis.
Yan et al. (2002) found that slightly lower levels of APC expression were associated with a pronounced predisposition to hereditary colorectal tumors. No APC mutations were identified in a family with FAP associated with partial reduction in APC protein expression, but neoplastic tissue showed loss of the normal allele. Yan et al. (2002) identified a second case with no structural changes in the APC gene, but a reduced level of expression of APC. The mutations responsible for the reduced expression presumably resided deep within an intron or far upstream of the gene in the affected allele. The data were consistent with a threshold for APC product being required to suppress intestinal tumorigenesis, and suggested that the threshold is finely balanced.
Albuquerque et al. (2002) analyzed somatic APC point mutations and LOH in 133 colorectal adenomas from 6 FAP patients. They observed that when germline mutations resulted in truncated proteins without any of the 7 beta-catenin downregulating 20-amino acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retained 1 or, less frequently, of the same 20-amino acid repeats. Conversely, when the germline mutation resulted in a truncated protein retaining one 20-amino acid repeat, most second hits removed all 20-amino acid repeats. The latter was frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retained 2 such repeats, the majority of the somatic hits were point mutations (and not LOH) located upstream, which removed all of the 20-amino acid repeats. These results indicated selection for APC genotypes that are likely to retain some activity in downregulating beta-catenin (116806) signaling. The authors proposed that this selection process is aimed at a specific degree of beta-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all of the beta-catenin downregulating motifs in APC.
Heppner Goss et al. (2002) demonstrated that APC alleles with 5-prime mutations produce APC protein that downregulates beta-catenin, inhibits beta-catenin/T-cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrated that cap-independent translation is initiated internally at an AUG at codon 184 of APC. Furthermore, APC coding sequence between AAPC mutations and AUG-184 permits internal ribosome entry in a bicistronic vector. These data suggested that AAPC alleles in vivo may produce functional APC by internal initiation and established a functional correlation between 5-prime APC mutations and their associated clinical phenotype.
A genetic model for colorectal cancer (Fearon and Vogelstein, 1990) suggests that the sequential accumulation of mutations in specific genes, i.e., APC, KRAS (KRAS2; 190070), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. However, Smith et al. (2002) found that only 6.6% of 100 colorectal cancer tumors had mutations in all 3 genes, with 38.7% of tumors containing mutations in only 1 of the 3 genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and KRAS were extremely rare. Statistical analysis confirmed that mutations in KRAS and p53 cooccurred less frequently than expected by chance. The findings suggested that these mutations lie in alternate pathways, and that there are multiple genetic pathways to colorectal cancer.
Green and Kaplan (2003) found that conditional expression of a truncated form of APC in HEK293 cells, which express wildtype APC, dominantly interfered with microtubule plus-end attachments, recapitulating the phenotype observed in APC mutant tumor cells. The authors proposed that APC functions to modulate microtubule plus-end attachments during mitosis, and that a mutant APC allele predisposes cells to increased mitotic abnormalities, which may contribute to tumor progression.
Kawasaki et al. (2003) showed that overexpression of ASEF (605216) decreased E-cadherin-mediated cell-cell adhesion and promoted the migration of epithelial canine kidney cells. Both of these activities were stimulated by truncated APC proteins expressed in human colorectal tumor cells. Experiments based on RNA interference and dominant-negative mutants showed that both ASEF and mutated APC were required for the migration of colorectal tumor cells expressing truncated APC. Kawasaki et al. (2003) concluded that the APC-ASEF complex functions in cell migration as well as in E-cadherin-mediated cell-cell adhesion, and that truncated APC present in colorectal tumor cells contributes to their aberrant migratory properties.
Takacs et al. (2008) demonstrated that Drosophila APC homologs have an activating role in both physiologic and ectopic Wnt/Wingless (see 164820) signaling. The Apc amino terminus is important for its activating function, whereas the beta-catenin binding sites are dispensable. Takacs et al. (2008) suggested that APC likely promotes Wingless transduction through downregulation of Axin (603816), a negative regulator of Wingless signaling. Takacs et al. (2008) suggested that, given the evolutionary conservation of APC in Wnt signal transduction, an activating role may also be present in vertebrates with relevance to development and cancer.
In FAP, beta-catenin is stabilized constitutively, providing a permanent mitogenic signal to normally resting cells. This occurs when the second allele of APC is inactivated somatically. Kohler et al. (2009) described an APC domain, the beta-catenin inhibitory domain (CID), that is located between the second and third 20-amino acid beta-catenin-binding repeats and therefore was present in many truncated APC products found in human tumours. In truncated APC, the CID was absolutely necessary to downregulate the transcriptional activity and the level of beta-catenin, even when an axin/conductin binding site was present. The activity of the CID was dramatically reduced in several colon cancer cell lines and could be inhibited by shorter truncated APC lacking the CID. The authors concluded that CID is a direct target of the selective pressure acting on APC during tumorigenesis, and it explains the interdependence of both APC mutations in colorectal, duodenal, and desmoid tumours.
Zhang et al. (2010) showed that deficiency in the APC gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (603599) expression through activation of c-Myc (190080), and that all-trans-retinyl acetate (RAc) independently upregulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; 603598) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, Zhang et al. (2010) showed that short-term and noncontinuous TRAIL and RAc treatment induced apoptosis specifically in intestinal polyps, strongly inhibited tumor growth, and prolonged survival in 'multiple intestinal neoplasms' (Min) mice. With their approach, Zhang et al. (2010) further demonstrated that TRAIL and RAc induced significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.
Lane et al. (2010) found evidence of reduced APC expression in patients with 5q- syndrome (153550) compared with healthy controls and patients with low-risk myelodysplastic syndrome.
Miclea et al. (2011) found that knockdown of Apc in mouse KS483 mesenchymal stem cell-like cells resulted in a thin, elongated spindle-shape morphology compared with the polygonal, cuboidal shape of control cells. Apc-knockdown cells had decreased proliferation rate, increased apoptosis, and increased Wnt/beta-catenin signal transduction compared with controls. Apc-knockdown cells had no chondrogenic or adipogenic differentiation potential. Osteogenic differentiation potential was impaired in Apc-knockdown cells, but the impairment could be counteracted by high concentrations of Bmp7 (112267). Further analysis showed increased BMP signaling in Apc-knockdown cells.
Germline and APC Somatic Mutations in Familial Adenomatous Polyposis 1
In 4 unrelated patients with familial adenomatous polyposis-1 (FAP1; 175100), Groden et al. (1991) identified 4 different heterozygous inactivating mutations in the APC gene (611731.0001-611731.0004).
In the germline of 5 patients with FAP1 or Gardner syndrome, Nishisho et al. (1991) identified 4 point mutations in the APC gene (611731.0005-611731.0008) using both the ribonuclease (RNase) protection assay on PCR-amplified DNA and direct sequencing of cloned PCR products. One mutation (611731.0006) was found in 2 unrelated patients: 1 with isolated FAP and the other with Gardner syndrome. Nishisho et al. (1991) also identified somatic mutations in the APC gene (see, e.g., 611731.0009) in 4 of 158 colorectal cancers isolated from patients with sporadic disease.
Miyoshi et al. (1992) identified germline mutations in the APC gene in 53 (67%) of 79 unrelated FAP patients. Twenty-eight mutations were small deletions and 2 were insertions of 1 or 2 bp; 19 were point mutations resulting in stop codons, and 4 were missense point mutations. Thus, 92% of the mutations were predicted to result in truncation of the APC protein. More than two-thirds (68%) of the mutations were clustered in the 5-prime half of the last exon, and nearly two-fifths of the total mutations occurred at 1 of 5 positions. The findings suggested that the C terminal of the protein is required for proper function.
Using denaturing gradient gel electrophoresis (DGGE), Fodde et al. (1992) identified 8 different germline mutations in the APC gene (see, e.g., 611731.0012-611731.0018) in Dutch patients with FAP. All the mutations resulted in truncated proteins.
Seki et al. (1992) identified LOH at the APC locus in an adrenocortical carcinoma from an FAP patient. Miyoshi et al. (1992) described loss of heterozygosity at the APC locus in 30 (48%) of 63 colorectal adenomas or carcinomas tumors, as well as somatic APC mutations in 43. Forty-one (95%) of the mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations were clustered within a small region of exon 15 designated as the 'mutation cluster region' (MCR), which accounted for less than 10% of the coding region. Mutations in the MCR result in expression of COOH-terminally truncated proteins. Combining all the data, more than 80% of tumors had at least one mutation in the APC gene, of which more than 60% had 2 mutations. The results strongly suggested that somatic mutations of the APC gene are associated with the development of the great majority of colorectal tumors.
Using SSCP analysis, Cottrell et al. (1992) identified APC mutations in patients with FAP and in colon cancer tissue from patients with sporadic disease. All mutations resulted in truncated proteins. Their results suggested that highly localized short sequences, such as runs that code for adenine and thymine, may account for up to 20% of all observed APC mutations. One 5-bp deletion was found in a sporadic colon tumor and in 4 unrelated APC patients. Cottrell et al. (1992) suggested that since most mutations predict truncation of the APC protein, diagnosis might be more conveniently detected through analysis of the APC protein.
Sen-Gupta et al. (1993) reported a somatic deletion mutation of the APC gene in desmoid tissue in a patient reported by Hodgson et al. (1993) as having FAP caused by a constitutional chromosome 5q22 deletion.
Nagase and Nakamura (1993) summarized the germline APC mutations in 174 FAP patients and in somatic APC mutations in 103 colorectal tumors, as well as mutations in tumors arising in organs other than the colon and rectum. They concluded that inactivation of both alleles at the APC locus is required for development of most tumors in the colon and rectum. The great majority of the known mutations would result in truncation of the APC product. Almost all known mutations had been located within the 5-prime half of the coding region, although somatic mutations in colorectal tumors tended to cluster in the MCR, which represents only 8% of the coding sequence (codons 1286-1513). It was suggested that the location of germline mutations is correlated with the number of colorectal polyps in FAP patients.
De Vries et al. (1996) described an on-line database of mutations in the APC gene. Beroud and Soussi (1996) described a database of germline and somatic mutations in the APC gene in human tumors and cell lines. The database held 737 mutations, including 332 germline and 402 somatic. Almost all led to truncation of the APC protein either by a nonsense mutation (30%) or by a frameshift mutation (68%). Most of the mutations occurred in the first half of the coding region. Germline mutations were scattered throughout the 5-prime half of the gene, whereas somatic mutations (60%) were concentrated in the MCR region. In germline mutations, 2 hotspot codons were identified, one at position 1061 and the second at position 1309. In somatic mutations, 2 hotspots occurred at positions 1309 and 1450. The authors noted that the concentration of mutations in the 5-prime part of the gene was believed to be involved in a dominant effect of the N-terminus of the APC protein. This APC region contains a dimerization domain and it has been demonstrated that wildtype and mutant APC are associated in vivo.
Van der Luijt et al. (1997) identified 67 germline mutations, including 27 novel mutations, in the APC gene in 105 Dutch families with FAP. Sixty-five mutations were detected using denaturing gradient gel electrophoresis (DGGE) for exons 1-14, and the protein truncation test for the large exon 15. Most of the mutations were either frameshifts (39/65) or single base substitutions (18/65), resulting in premature stop codons. Splicing defects were identified in 7 cases and a nonconservative amino acid change in 1 case. Southern blot analysis detected APC structural rearrangements in 2 pedigrees by Southern blot analysis.
Analyzing 2 sets of data, Marshall et al. (1997) commented on the finding that 1- to 2-bp deletions and 1-bp insertions were much more commonly found among somatic mutations of the APC gene than among germline mutations of the APC gene. On the other hand, deletions of more than 2 bp were much more frequent among the germline mutations than among somatic mutations. Insertions of more than 1 bp were more frequent in somatic mutations than in germline mutations. Possible explanations for these differences were discussed.
Wallis et al. (1999) carried out mutation analysis of the APC gene in 205 families, composed of 190 unrelated FAP and 15 non-FAP colorectal cancer patients, using DGGE, PTT, and direct sequencing. Mutations causing chain termination were identified only in patients in the FAP group (105 patients). Amino acid substitutions were identified in 4 individuals, 3 of whom were in the non-FAP group.
Won et al. (1999) identified germline mutations of the APC gene in 38 of 62 (61%) unrelated Korean patients with FAP. The mutation was presumed to be novel in 19. They found the protein truncation test to be superior to SSCP analysis in the detection of germline mutations.
Approximately 80% of FAP patients can be shown to have truncating mutations of the APC gene. To determine the cause of FAP in the other 20% of the patients, Laken et al. (1999) used MAMA (monoallelic mutation analysis) to examine independently the status of each of the 2 APC alleles. Of 9 patients analyzed, 7 were found to have significantly reduced expression from 1 of their 2 alleles, whereas 2 patients were found to have full-length expression from both alleles. Laken et al. (1999) concluded that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FAP patients argues strongly against the requirement for dominant-negative effects of APC mutations. The results also suggested that there may be at least 1 additional gene besides APC that can give rise to FAP. Laken et al. (1999) pointed out that APCL, a homolog of APC located on 19p13.3, had been described by Nakagawa et al. (1998) and van Es et al. (1999). This homolog, as well as the functionally related family of axin genes (see 603816), are good candidates for FAP causation in these kindreds.
In 4 FAP families, Su et al. (2000) identified pathogenic APC genomic rearrangements resulting from homologous and nonhomologous recombinations mediated by Alu elements. Two of these 4 rearrangements were complex, involving deletion and insertion of nucleotides. These rearrangements were initially revealed by analyzing cDNAs and could not have been identified by using mutation detection methods that screened each exon individually. The identification of 4 genomic rearrangements among a total of 26 APC mutations in the study suggested that genomic rearrangements are relatively frequent.
Lamlum et al. (2000) screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to 3 Ashkenazi patients with I1307K (611731.0029), they found 7 patients with the E1317Q variant (611731.0036) and 4 patients with truncating APC variants in exon 9 or in the 3-prime part of the gene. Germline APC variants accounted for approximately 10% of patients with multiple adenomas. The authors recommended screening multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumors, for truncating mutations 5-prime to exon 5, in exon 9, and 3-prime to codon 1580.
In 34 of 917 unrelated FAP patients, Aretz et al. (2004) identified 26 different heterozygous mutations in the APC gene at or close to splice sites; 6 of these occurred within exon sequences. Detailed analysis showed that 1 variant in exon 4 and 3 variants in exon 14 resulted in exon skipping due to aberrant splicing, likely related to disruption of exonic splicing enhancers. Aretz et al. (2004) emphasized that the consequences of some missense and silent mutations are manifest at the DNA level and not the protein level. Aretz et al. (2004) found that a common 5-bp deletion at codon 1309 (611731.0023) was overrepresented in their group of patients with proven or suspected de novo mutations compared with familial cases (34 of 96 vs 26 of 505, p less than 0.001), supporting the view that the sequence around codon 1309 is a hotspot for mutation. Using haplotype analysis, Aretz et al. (2004) traced the parental origin of de novo mutations in 16 unrelated patients and found that 4 were of maternal and 12 of paternal origin, suggesting a moderate sex bias towards paternal origin. They noted that large deletions and single-base substitutions were exclusively of paternal origin, whereas small deletions were equally distributed.
Among tissue specimens from 174 FAP patients with known APC germline mutations, Blaker et al. (2004) identified 8 tumors of types infrequently seen in FAP. Second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of beta-catenin, but no mutations in the CTNNB1 gene. Blaker et al. (2004) stated that theirs was the first study reporting second somatic APC mutations in FAP-associated uterine adenocarcinoma and epidermal cysts, and concluded that their data strengthened a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients.
Aretz et al. (2005) used the multiplex ligation-dependent probe amplification (MLPA) method to screen 174 unrelated FAP patients in whom no point mutation in the APC gene had been uncovered by PTT or denaturing high-performance liquid chromatography (DHPLC). They identified 14 different deletions in 26 patients, ranging from single exons to the whole gene including the promoter region. Almost all of the deletions (22 of 26) were detected in the 46 patients with typical FAP, whereas none were found in 93 patients with attenuated FAP. Aretz et al. (2005) noted that a large deletion occurred in about half of the apparently mutation-negative families with typical FAP, pointing to an overall frequency of around 12% for large deletions in their series of patients with typical FAP, compared to 75% for point mutations.
Charames et al. (2008) identified a large heterozygous deletion in the APC promoter region, including promoter 1A and 5-prime untranslated regions, in affected members of a large Canadian Mennonite kindred with adenomatous polyposis coli and colon cancer. The authors were unable to determined the precise limits of the large promoter deletion. The mutation was shown to result in transcriptional silencing of the APC allele. The findings were consistent with a founder effect in this genetically isolated population.
Vermeulen et al. (2013) quantified the competitive advantage during tumor development of Apc loss, Kras (190070) activation, and p53 (191170) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, Vermeulen et al. (2013) found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. Vermeulen et al. (2013) concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.
Li et al. (2016) confirmed a heterozygous c.-192A-T mutation (611731.0056) in 8 French FAP families reported by Lagarde et al. (2010). Li et al. (2016) noted that although fundic gland polyps (FGPs) were prominent in the French families, all probands and many family members had undergone colectomy for florid colonic polyposis, differentiating the condition in these patients from GAPPS (see later). In addition, Li et al. (2016) studied another FAP family with profuse FGPs as well as colorectal polyposis in which all 5 affected members were heterozygous for a c.-190G-A mutation in the APC promoter 1B (611731.0057).
Desmoid Disease
In affected members of the family reported by Maher et al. (1992) with desmoid disease (DESMD; 135290), Scott et al. (1996) identified a germline deletion in the APC gene (611731.0026). Affected members of 2 other apparently unrelated families with desmoid tumors had the same mutation, and haplotype analysis suggested a common origin. Scott et al. (1996) concluded that FAP and hereditary desmoid disease are allelic, and that APC mutations that truncate the APC protein distal to the beta-catenin-binding domain are associated with desmoid tumors, absence of congenital hypertrophy of the retinal pigment epithelium, and variable but attenuated polyposis expression.
In affected members of a family with hereditary desmoid disease, Eccles et al. (1996) identified a heterozygous germline mutation in the 3-prime end of exon 15 of the APC gene (611731.0025). There was somatic loss of the wildtype APC allele within several desmoid tumors.
Halling et al. (1999) identified a truncating mutation in the APC gene (611731.0040) in affected members of an Amish family with autosomal dominant desmoid disease.
Gastric Adenocarcinoma and Proximal Polyposis of the Stomach
In a large 5-generation Australian family segregating autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), Li et al. (2016) identified a point mutation and a 1-bp deletion (c.-195A-C and c.-125delA; 611731.0053), both located on the same allele of the APC promoter 1B, that completely cosegregated with disease in the family. Analysis of 5 additional families revealed a heterozygous c.-191T-C variant (611731.0054) segregating with disease in 4 of the families, and a heterozygous c.192A-G change (611731.0055) in both affected members of the remaining family. The changes were not found in public variant databases. Analysis of fundic gland polyps from the Australian family confirmed the germline promoter 1B mutations and also revealed 4 somatic truncating APC mutations, present at estimated mutant allele frequencies of 31%, 12%, 9% and 8%. Li et al. (2016) proposed that APC haploinsufficiency is responsible for the fundic gland polyposis, whereas the second APC hit might be the driver of dysplasia.
In affected members of a 3-generation Czech family segregating autosomal dominant GAPPS, Repak et al. (2016) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In a 38-year-old Austrian woman with GAPPS, Beer et al. (2017) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In 24 individuals from 8 Czech families with GAPPS, Foretova et al. (2019) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In affected members of 2 multiplex Japanese families with GAPPS, Kanemitsu et al. (2021) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
Other Cancers Caused by Somatic Mutation in the APC Gene
Oda et al. (1996) observed loss of heterozygosity (LOH) at the APC and/or MCC loci in 4 (57%) of 7 informative hepatoblastoma (see 114550) tissues derived from patients without FAP. Somatic mutations were detected in 8 (61.5%) of the 13 total cases, with 9 cases (69%) showing genetic alterations in the APC gene as LOH or somatic mutations (see, e.g., 611731.0024). Double mutations were demonstrated in 2 cases. The nature of the somatic mutations observed in this study was unusual because 9 of the 10 mutations were missense, with only 1 case featuring a frameshift mutation due to an insertion. By contrast, more than 90% of mutations in the APC gene in colorectal tumors result in a truncated APC protein due to either frameshift or nonsense mutations.
Among 46 medulloblastomas (see 155255) derived from patients with sporadic disease and no FAP, Huang et al. (2000) identified 2 with somatic mutations in the APC gene and 4 with somatic mutations in the beta-catenin gene. This study provided the first evidence that APC mutations are operative in a subset of sporadic medulloblastomas.
Epigenetics
In a study of patients with stage I nonsmall cell lung cancer (see 211980) who underwent curative resection but had a recurrence compared to matched patients who did not have a recurrence, Brock et al. (2008) found that promoter methylation of the CDKN2A (600160), CDH13 (601364), RASSF1A (605082), and APC genes in tumors and in histologically tumor-negative lymph nodes was independently associated with tumor recurrence.
In 22 unrelated APC patients, Nagase et al. (1992) found that germline mutations between codons 1250 and 1464 were associated with profuse polyps (10 or more), whereas mutations in other regions of the APC gene were associated with sparse polyps (fewer than 10).
In an analysis of 150 unrelated patients with familial adenomatous polyposis, Nagase et al. (1992) found no indication that extracolonic manifestations, such as osteomas and desmoid tumors, correlated with the type or intragenic location of a particular germline mutation.
Olschwang et al. (1993) found that the extent of congenital hypertrophy of the retinal pigment epithelium (CHRPE) correlated with the position of the protein-truncating mutation in APC. CHRPE lesions were almost always absent if the mutation occurred before exon 9, but were consistently present if it occurred after this exon. The same finding was recorded by Bunyan et al. (1995), who also noted that a more distal mutation site was associated with an earlier age of onset of symptoms and a larger number of colonic polyps.
Caspari et al. (1994) and Gayther et al. (1994) found that patients with the 5-bp deletion at codon 1309 (611731.0023) had gastrointestinal symptoms and death from colorectal cancer that occurred about 10 years earlier than in patients with other mutations.
Spirio et al. (1993) and Olschwang et al. (1993) found that the patients with mutations in codons 136 to 302 of the APC gene did not develop CHRPE, whereas those with mutations in a region beyond exon 9 and up to codon 1387 of the gene presented with ophthalmic lesions. Only some patients with mutations within exon 9 had CHRPE. Among 26 FAP patients, including 18 with CHRPE, Wallis et al. (1994) reported a clear association between CHRPE and APC mutations located at or after codon 457 in exon 9. Patients without CHRPE all had mutations proximal to exon 9. All 26 APC mutations resulted in truncated proteins, but the mutations associated with CHRPE predicted truncated proteins larger than 50 kD. Wallis et al. (1994) suggested that larger mutant APC proteins may exert a dominant-negative effect, resulting in decreased APC function and expression of CHRPE.
Among 36 patients from 20 FAP families, Caspari et al. (1995) found that patients with a mutation between codons 1445 and 1578 did not express CHRPE, but developed severe desmoid tumors. With the exception of 3 prepubertal children, all patients with mutations in this region developed desmoid tumors.
Davies et al. (1995) found that families with mutations 3-prime of codon 1444 had significantly more lesions on dental panoramic radiographs (p less than 0.001) and appeared to have a higher incidence of desmoid tumors than did families with mutations at the 5-prime end. All 7 families except one with mutations 5-prime of exon 9 did not express CHRPE. All of 38 individuals from 16 families with mutations between exon 9 and codon 1444 expressed CHRPE. The 11 individuals from 4 families with mutations 3-prime of codon 1444 did not express CHRPE. These results suggested that the severity of some of the features of Gardner syndrome may correlate with genotype in FAP.
Giardiello et al. (1997) studied 51 families in the Johns Hopkins Polyposis Registry and detected germline APC mutations in 42. APC mutation was associated with the extraintestinal phenotype. Mutations in codons 542-1309 were associated with pigmented retinal lesions, while mutations in codons 1465, 1546, and 2621 were associated with multiple extraintestinal manifestations. Patients without extraintestinal manifestations had either nontruncating APC mutations or had no detectable APC mutations.
Brensinger et al. (1998) examined the colorectal and extracolonic phenotypes in 2 FAP families from the Johns Hopkins Polyposis Registry; 1 family from the Indiana University Medical Center, Indianapolis, Indiana; and 1 from the University of Colorado Cancer Center, Denver, Colorado with mutations in the 3-prime end of the APC gene. The authors found considerable intra- and interfamilial variability in colorectal phenotype. Extracolonic manifestations also showed intra- and interfamilial variation and did not correlate with colorectal phenotypic expression: many of the individuals with an attenuated colorectal phenotype had numerous skin lesions. No clear genotype-phenotype correlation emerged from this study.
Wallis et al. (1999) studied genotype/phenotype correlations for 9 extracolonic manifestations associated with FAP. A significantly greater proportion of individuals with mutations between codons 1395 and 1493 (group C3) exhibited osteomas, desmoids, and epidermoid cysts as compared to those with mutations between codons 177 and 452 (group C1). In addition, a significantly greater proportion of group C3 patients presented with symptomatic desmoid tumors and osteomas as compared to those with mutations between codons 457 and 1309 (group C2). Patients in group C3 also exhibited the highest frequency of periampullary cancer and gastric and duodenal adenomas. Although the incidence of hepatoblastoma was too low to allow statistical analysis, Wallis et al. (1999) noted that hepatoblastoma-associated APC mutations clustered within the group C2 mutation region. Wallis et al. (1999) suggested that liver imaging may be indicated in families with mutations in this region.
Among 105 FAP patients with known pathogenic APC mutations, Bisgaard and Bulow (2006) found that 17 reported palpable osteomas. Osteomas were only identified in patients with mutations between codons 767 and 1513, a gene area also associated with CHRPE and hepatoblastoma. Sebaceous cysts were reported in 51% of 173 FAP patients, and those patients had APC mutations evenly distributed in the gene with no particular hotspots. Osteomas appeared most frequently in patients with sebaceous cysts (odds ratio of 6.6).
Attenuated APC
Spirio et al. (1993) determined the APC mutations in 7 families with so-called 'attenuated adenomatous polyposis coli' (AAPC), i.e., FAP with relatively few colonic polyps but still a significant risk of colon cancer. Four distinct mutations in the APC gene were identified in 7 AAPC families (see, e.g., Y157X, 611731.0021). These mutations predicted truncation products, similar to those identified in classic APC. However, 4 mutated sites in AAPC were located very close to one another and closer to the 5-prime end of the APC gene than mutations previously discovered in patients with classic APC.
Friedl et al. (1996) reported a large family with attenuated FAP with a frameshift mutation at codon 1597, which is beyond the beta-cadherin binding site. The findings suggested a 5-prime border for the occurrence of a second region of attenuated FAP that is located in the 3-prime part of the APC gene. The authors proposed that a sufficient amount of functional APC protein was available due to the absence of a dominant-negative effect.
In a large Dutch family with attenuated FAP, van der Luijt et al. (1996) identified a truncating mutation in the 3-prime region of the APC gene (exon 15) (611731.0028). No truncated polypeptides were detected in patient cells. Van der Luijt et al. (1996) speculated that 3-prime mutations may be null alleles and that the attenuated phenotype is the result of a haploinsufficiency of the normal APC protein and absence of a truncated protein that could lead to a dominant-negative effect.
Spirio et al. (1998) suggested that specific APC alleles may be able to modulate somatic APC chromosomal stability, including LOH. In 64 adenomas and 2 carcinomas from 8 patients with attenuated APC, there was a decreased LOH of the APC allele compared to tumors of patients with classic APC. In fact, no loss of the inherited normal APC allele was observed, although sequencing showed that the inherited normal APC allele had frequently undergone somatic point mutations and small deletions in the tumors. These findings supported the suggestion that attenuated APC alleles have residual gene activity and that this activity modulates the spectrum and frequency of downstream mutations that lead to adenoma formation.
In affected individuals from 7 of 11 AAPC kindreds, Soravia et al. (1998) identified 5 novel germline APC mutations. The mutations were located in 3 different regions of the APC gene: (1) at the 5-prime end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3-prime distal end of the gene. Patients with mutations at the 5-prime end of the gene tended to have more severe upper-gastrointestinal manifestations and a higher number of polyps compared to the other groups. All AAPC kindreds showed a predominance of right-sided colorectal adenomas and rectal polyp sparing. No desmoid tumors were found in these kindreds.
Su et al. (2000) investigated the mechanism for attenuated APC in patients carrying a mutant APC allele with a mutation in the alternatively spliced region of exon 9, designated APC-AS9. The APC-AS9 allele was found to downregulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wildtype APC. Mutation analysis showed that both APC-AS9 and the wildtype APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that a common somatic mutation in APC-AS9 in these tumors did not inactivate the wildtype APC. The results indicated that carriers of APC-AS9 develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients do develop colorectal tumors more frequently than does the general population because APC-AS9 is inactivated by mutations that do not inactivate the wildtype APC.
A further group of individuals, so-called 'multiple' adenoma patients, have a phenotype like AAPC, with 3 to 99 polyps throughout the colorectum, but most have no demonstrable germline APC mutations. Routine mutation detection techniques failed to detect a pathogenic APC germline mutation in approximately 30% of patients with classic polyposis and 90% of those with AAPC/multiple adenomas. Sieber et al. (2002) developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classic polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germline mutation, deletions were found exclusively in individuals with classic polyposis (7 of 60, 12%). Fine mapping of the region suggested that most (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classic polyposis phenotype.
The 3-prime 6.5 kb of the APC open reading frame is encoded by a single exon, exon 15. Su et al. (2002) characterized 2 germline APC alterations that deleted the entire APC exon 15 as a result of 56-kb (611731.0049) and 73-kb (611731.0050) deletions at the APC locus. A surprising finding was that the latter mutation resulted in a typical FAP phenotype, whereas the former resulted in a phenotype consistent with attenuated FAP.
Heppner Goss et al. (2002) demonstrated that attenuated APC alleles with 5-prime mutations produce APC protein that downregulates beta-catenin, inhibits beta-catenin/T-cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrated that translation was initiated internally at an AUG at codon 184. Furthermore, APC coding sequence between AAPC mutations and AUG-184 permitted internal ribosome entry in a bicistronic vector. These data suggested that AAPC alleles in vivo may produce functional APC by internal initiation. In addition, the amino terminus of APC, which includes a homodimerization domain and nuclear export signal, may not be critical for APC tumor-suppressor function.
During APC mutation screening in 1,248 unrelated FAP patients, Aretz et al. (2007) identified 75 cases with an assumed or confirmed de novo mutation, and in 8 (11%) of the de novo cases, they confirmed the presence of somatic mosaicism. In leukocyte DNA, the percentage of mosaicism varied between 5.5% and 77%, whereas the proportion of the mutation in tumor DNA from the respective patients was consistently higher. Six of the 8 patients had an attenuated or atypical polyposis phenotype that differed from the expected phenotype given the site of the mutation. Aretz et al. (2007) concluded that some of the deviations from the expected phenotype in FAP could be explained by the presence of somatic mosaicism.
Animal Models of Disease
Lander (1991) used his microsatellite map to locate the mouse 'multiple intestinal neoplasia' (Min) gene to mouse chromosome 18, which shows homology of synteny to human chromosome 5. The findings suggested that Min corresponds to APC in the human. Su et al. (1992) showed specifically that the murine homolog of the APC gene (Apc) is tightly linked to the phenotypically defined Min locus. In the Min mouse, the authors identified a nonsense mutation in the Apc gene: a 2549T-A transversion, resulting in a leu850-to-ter (L850X) substitution. Luongo et al. (1993) showed that Min maps to proximal mouse chromosome 18. Thus, Apc and Mcc are syntenic in both mouse and human, although the gene order in the interval between the 2 genes is different between the 2 species.
Fodde et al. (1994) found that mice heterozygous for a truncating Apc gene mutation progressively developed intestinal tumors in a manner similar to that observed in patients with FAP and in mice carrying the Min mutation. Moser et al. (1993) showed that female mice carrying the Min mutation were also prone to develop mammary tumors. Min/+ mammary glands were more sensitive to chemical carcinogenesis than are +/+ mammary glands. Transplantation of mammary cells from Min/+ or +/+ donors into +/+ hosts demonstrated that the propensity to develop mammary tumors was intrinsic to the Min/+ mammary cells.
Dietrich et al. (1993) reported the genetic mapping of a locus that strongly modified tumor number in Min/+ animals. This gene, Mom1 ('modifier of Min1'; 172411), mapped to distal chromosome 4 and controlled about 50% of genetic variation in tumor number in 2 intraspecific backcrosses. It was found to lie in the region of synteny conservation with human chromosome 1p36-p35, a region of frequent somatic loss of heterozygosity in a variety of human tumors, including colon tumors.
Using homologous recombination of Apc in embryonic stem cells to generate mice with a truncated Apc protein, Oshima et al. (1995) found that most homozygous mice died in utero before day 8 of gestation. Heterozygous mice developed multiple polyps throughout the intestinal tract, mostly in the small intestine. The earliest polyps arose multifocally during the third week after birth, and new polyps continued to appear thereafter. Surprisingly, every nascent polyp consisted of a microadenoma covered with a layer of normal villous epithelium. These microadenomas originated from single crypts by forming abnormal outpockets into the inner lacteal side of the neighboring villi. Genotyping showed that all microadenomas had lost the wildtype Apc allele, whereas the mutant allele remained unchanged. These results indicated that loss of heterozygosity followed by formation of intravillous microadenomas was responsible for polyposis in the intestinal mucosa. A dominant-negative mechanism was considered unlikely.
In the Min mouse, Wasan et al. (1997) observed a small but general increase in tumor counts in both the large and the small bowel with higher dietary fat. Increasing dietary fat also increased polyp size in the small bowel. These changes appeared independent of total calorific intake as assessed by body weights. Halving the crude fiber intake together with an increase in dietary fat from 3% to 10% did not have as marked an effect on tumor counts as did an increase of fat alone to 15%, which also decreased survival.
Takaku et al. (1998) inactivated the mouse Dpc4 gene (SMAD4; 600993). The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality. These investigators then introduced the Dpc4 mutation into the knockout mice for the mouse Apc-delta716 gene. Because both Apc and Dpc4 are located on mouse chromosome 18, they constructed compound heterozygotes carrying both mutations on the same chromosome by meiotic recombination. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc-delta716 heterozygotes, showing an extensive stromal cell proliferation, submucosal invasion, cell type heterogeneity, and in vivo transplantability. Takaku et al. (1998) suggested that mutations in DPC4 (SMAD4) play a significant role in the malignant progression of colorectal tumors.
Fodde et al. (2001) found that mouse embryonic stem cells with a mutant Apc gene showed extensive chromosome and spindle aberrations, suggesting a role for APC in chromosome segregation. Consistent with this role, wildtype APC accumulated at the kinetochore during mitosis. Mutant Apc cells formed mitotic spindles with an abundance of microtubules that inefficiently connected with kinetochores. This phenotype could be recapitulated by the induced expression of a 253-amino acid carboxy-terminal fragment of APC in microsatellite-unstable human colorectal cancer cells. Fodde et al. (2001) concluded that loss of APC sequences that lie C-terminal to the beta-catenin regulatory domain contributes to chromosomal instability in colorectal cancer.
Kielman et al. (2002) investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. They provided genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the 3 germ layers was inhibited by increased doses of beta-catenin (116806) by specific Apc mutations. These ranged from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal, and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Ctnnb1 (Catnb) also affected the differential potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supported the differentiation defects at the molecular level and pinpointed a large number of downstream structural and regulating genes. Chimeric experiments showed that the effect was cell-autonomous. The results implied that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues.
The mammalian homeobox transcription factor CDX2 (600297) has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop 1 or 2 benign hamartomas in the proximal colon, whereas heterozygous Apc(del716) mice develop numerous adenomatous polyps, mostly in the small intestine. Aoki et al. (2003) showed that the colonic polyp number is about 6 times higher in compound mutant mice carrying both mutations in heterozygous state. Levels of both Apc and Cdx2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity at Apc. In cultured rat intestinal epithelial and human colon cancer cell lines, suppression of Cdx2 by antisense RNA caused marked increases in ABI and chromosomal aberrations. This was mediated by stimulation of the mTOR (601231) pathway, causing translational deregulation and G1-S acceleration. Similar results were obtained in the mice with compound heterozygosity for the Apc deletion and the Cdx knockout. Forced activation of mTOR through the upstream regulator Akt1 (164730) also increased ABI in colon cancer cells. High ABI in all cell lines was suppressed by mTOR inhibitors. These results suggested that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability.
Functional loss of APC has been shown or proposed to have several different mechanisms: mutation in APC, nondisjunction, homologous somatic recombination, and epigenetic silencing. In the C57BL/6 (B6) Apc(Min/+) mouse model of inherited intestinal cancer, loss of Apc function can occur by loss of heterozygosity through somatic recombination between homologs. Haigis and Dove (2003) reported that the Robertsonian translocation referred to as Rb9 suppressed the multiplicity of intestinal adenomas in this mouse model. As the copy number of Rb9 increased, the association with the interphase nucleolus of the rDNA repeats centromeric to the Apc locus on mouse chromosome 18 was increasingly disrupted. Their analysis showed that homologous somatic recombination is the principal pathway for LOH in adenomas in B6 Apc(Min/+) mice. These studies provided additional evidence that neoplastic growth can initiate in the complete absence of canonic genomic instability. Rb9 was originally identified in a wild mouse caught in the Orobian Alps near Bergamo in northern Italy. It consists of a centric fusion between mouse chromosomes 7 and 18. In addition to reduced fertility owing to meiotic nondisjunction, the chromosomes involved in a Robertsonian translocation show suppressed meiotic recombination when heterozygous. The suppression of recombination is thought to result from mispairing of trivalents during pachytene.
Tischfield and Shao (2003) pointed to the work of Haigis and Dove (2003) as indicating that somatic recombination rather than chromosome loss associated with genetic instability is the primary cause of adenoma formation in the mouse model. The authors showed that a Robertsonian translocation, which seemingly interferes with the colocalization of chromosome homologs in interphase nucleus, suppresses recombination and subsequent adenoma formation in the mutant mice. Karyotypically normal B6 mice heterozygous for the Min mutation of the Apc gene have intact nucleolar organizing regions (NORs) near the centromeres of chromosome 18 homologs, facilitating nucleolar colocalization and the homologous recombination that produces loss of a normal Apc allele and a high incidence of intestinal adenomas. Apc(Min+) mice lack an NOR on the 7.18 translocation chromosome, resulting in a failure of nucleolar colocalization of homologs, suppression of homologous recombination, and far fewer intestinal adenomas.
Hurlstone et al. (2003) found that Apc mutant zebrafish completed gastrulation, but their hearts failed to loop and formed excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf-1 (DKK1; 605189), a secreted Wnt inhibitor, blocked cushion formation. In wildtype hearts, nuclear beta-catenin accumulated only in valve-forming cells, where it could activate a Tcf reporter. In mutant hearts, all cells displayed nuclear beta-catenin and Tcf reporter activities, while valve markers were markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occurred throughout the endocardium. Hurlstone et al. (2003) concluded that Wnt/beta-catenin signaling may play a role in determining endocardial cell fate. Apc mutant zebrafish carried a premature termination codon corresponding to amino acid 1318 of human APC, an allele designated apc(mcr). Heterozygous mutant zebrafish developed normally. Homozygous mutant zebrafish embryos died between 72 and 96 hours postfertilization and displayed multiple defects including cardiac malformations, enlarged otic vesicles, smaller eyes, and body curvature. Further, jaw, pharynx, and inner-ear structures failed to develop and fin buds arrested. Primordia for internal organs such as gut, liver, and pancreas formed but developed abnormally. Hurlstone et al. (2003) suggested that mutant embryos probably develop beyond gastrulation owing to the presence of maternal Apc.
Rao et al. (2005) found that mice haploinsufficient for both Bub1b (602860) and Apc developed 10 times more colonic tumors than mice deficient in Apc alone, and the tumors were of higher grades. Compound mutant mouse embryonic fibroblasts (MEFs) contained more beta-catenin and proliferated at a faster rate than wildtype or Bub1b +/- MEFs. Compound mutant MEFs also slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than wildtype, Bub1b +/-, or Apc +/- mice. Rao et al. (2005) concluded that BUB1B and APC functionally interact in regulating metaphase-anaphase transition, deregulation of which increases genomic instability and the development and progression of colorectal cancer.
Nadauld et al. (2006) found that Apc mutant zebrafish had ocular abnormalities similar to those in mice and humans with APC mutations. Furthermore, they showed that Apc had a dual role in ocular morphogenesis. APC regulation of canonical WNT/beta-catenin signaling appeared active in the developing lens. In contrast, Apc controlled retinoic acid production via Rdh5 in the retina and was required for retinal differentiation.
Amos-Landgraf et al. (2007) established a nonsense mutation of the Apc gene in an inbred rat strain and observed that Apc-mutant heterozygotes developed multiple neoplasms with a distribution between the colon and small intestine that closely simulated that found in human FAP patients. Owing to the metacentric nature of the rat karyotype, the authors were able to demonstrate that loss of the wildtype APC allele in tumors did not involve chromosome loss. Amos-Landgraf et al. (2007) designated this rat strain Pirc (polyposis in rat colon) and suggested that it could address many of the gaps in modeling human colon cancer.
To elucidate the role of MYC (190080) in the intestine after APC loss, Sansom et al. (2007) simultaneously deleted both Apc and Myc in the adult murine small intestine. They showed that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation, and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt (see 164820) target gene activation following Apc loss. Sansom et al. (2007) concluded that these data established MYC as the critical mediator of the early stages of neoplasia following APC loss.
Shibata et al. (2007) generated several FAP mouse lines heterozygous for a ser580-to-asp (S580D) truncation mutation in the Apc gene and found that 1 line (line 19) showed reduced incidence of intestinal adenomas (less than 5% compared with other lines). They identified a deletion in the Ctnna1 gene (116805) as the cause of tumor suppression in line-19 Apc S580D/+ mice and found that suppression only occurred when the Ctnna1 deletion was in cis configuration with the Apc S580D mutation. In all adenomas generated in line-19 Apc S580D/+ mice, somatic recombination between Apc and Ctnna1 retained the wildtype Ctnna1 allele. Shibata et al. (2007) concluded that simultaneous inactivation of Ctnna1 and Apc during tumor initiation suppressed adenoma formation in line-19 Apc S580D/+ mice, suggesting that CTNNA1 plays an essential role in initiation of intestinal adenomas.
Miclea et al. (2009) found that conditional knockout of Apc in Col2a1 (120140)-expressing cells in mice resulted in accumulation of cytoplasmic beta-catenin in skeletal precursors, leading to impaired embryogenesis and perinatal lethality. Examination of endochondral bone formation showed that mutant skeletal precursor cells failed to differentiate into chondrogenic and osteogenic lineages. However, skeletal precursors could differentiate and form functional osteoblasts with mineral deposition in developing proximal rib. The high level of beta-catenin due to loss of Apc did not result in chondrocyte maturation, but it led to chondrocyte dedifferentiation in the nasal septum, indicating that Apc is required to suppress beta-catenin for maintenance of the chondrocytic phenotype.
Lane et al. (2010) showed that young Apc(min) mice had normal steady-state hematopoiesis. However, Apc(min) mice developed myelodysplastic syndrome between 136 and 210 days of age, with increased potential for spleen cells to form myeloid, granulocyte, and erythroid colonies. Transplantation experiments revealed that Apc(min) bone marrow had enhanced repopulation potential, suggesting intrinsic enhancement of short- and long-term hematopoietic stem cell function. However, serial transplantation experiments revealed impaired repopulation potential in secondary recipients due to loss of the quiescent stem cell population in Apc(min) bone marrow.
Therapeutic Strategies
Westbrook et al. (1994) explored the potential for gene therapy by studying the transient expression of the APC gene in normal rat colonic epithelium, using liposomal gene delivery by rectal catheter infusion. Expression of a beta-galactosidase reporter gene and of the human APC gene under a constitutive promoter was demonstrated. Close to 100% of epithelial cells expressed the introduced gene. Expression was transient and did not persist beyond 4 days, consistent with the normal turnover time of gut epithelium, but it could be maintained by repeated treatments. Human APC was expressed for 3 weeks under these conditions at approximately one-tenth the level of the endogenous APC gene, and no toxicity was observed beyond that attributed to repeated rectal enemas.
Tsujii and DuBois (1995) showed that overexpression of cyclooxygenase-2 (COX2; 600262) in rat intestinal epithelial cells resulted in increased adhesion to extracellular matrix and resistance to butyrate-induced apoptosis. These phenotypic changes that might enhance tumorigenic potential were reversed by sulindac sulfide, a COX inhibitor.
Mahmoud et al. (1997) found that heterozygous Min -/+ mice with an Apc mutation resulting in a truncated Apc protein had changes in the growth characteristics of preneoplastic tissue, including decreased apoptosis and proliferation and decreased enterocyte migration. These findings suggested a dominant-negative effect. The mutation was also associated with changes in beta-catenin expression. These effects were reversed with the chemopreventive drug sulindac sulfide. However, Mahmoud et al. (1999) found no difference in enterocyte migration, proliferation, apoptosis, or beta-catenin levels in another group of mutant Apc mice with no Apc protein expression compared to wildtype littermates bearing 2 normal Apc alleles. Furthermore, administration of sulindac sulfide to Apc1638N mice did not alter enterocyte migration. These observations suggested that the dominant-negative effect altering cell migration was exerted by the truncated Apc protein present in the first group of Min/+ mice.
Boolbol et al. (1996) found that histologically normal-appearing small bowel from the Min mouse showed increased amounts of Cox2 and prostaglandin E2 compared to +/+ littermates. Using 2 different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27%-47% decrease in enterocyte apoptosis compared to +/+ animals. Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox2 and prostaglandin E2 to baseline and restored normal levels of apoptosis.
Oshima et al. (1996) bred mice carrying an APC mutation with a mouse with a disrupted Cox2 gene. All of the animals were heterozygous at the Apc locus; if homozygous for wildtype COX2, they developed an average of 652 polyps at 10 weeks, while heterozygotes had 224 polyps and homozygously deficient mice had only 93 polyps. The findings showed that induction of Cox2 is an early, rate-limiting step for adenoma formation. As supporting evidence, a drug that inhibited COX2 but not COX1 (176805) also markedly reduced the number of polyps. Oshima et al. (1996) added the Cox2 gene to the list of genes involved in colon neoplasia. The findings suggested to Prescott and White (1996) that drugs that inhibit COX2 should be broadly effective in chemoprevention of colon cancer. Prescott and White (1996) reviewed the intimate connections between APC and COX2.
Halberg et al. (2000) found that the multiplicity and invasiveness of intestinal adenomas in Min mice was enhanced by deficiency of p53. In addition, the occurrence of desmoid fibromas was strongly enhanced by p53 deficiency. The genetic modifier Mom1 and the pharmacologic agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function. Mom1 showed no influence on the development of desmoid fibromas, whereas the combination of piroxicam and difluoromethylornithine exerted a moderate effect.
Lal et al. (2001) studied the effects of COX inhibitors on intestinal adenomas and colonic aberrant crypt foci in the accelerated polyposis mismatch-repair-deficient Min mouse model (Apc+/-Msh2-/-) as well as in the standard Min mouse model. The mice with knockout of the Msh2 gene (609309) have genetic features of both familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, and rapidly develop numerous small- and large-bowel adenomas, as well as colonic aberrant crypt foci. Lal et al. (2001) found that a specific COX2 inhibitor was effective in preventing small-bowel polyps in mismatch-repair-deficient Min mice and both small- and large-bowel polyps in standard Min mice.
In a patient with familial adenomatous polyposis coli-1 (FAP1; 175100), Groden et al. (1991) identified a heterozygous 2-bp deletion at exon 7 of the APC gene at positions 730 and 731 in the cDNA sequence reported by Joslyn et al. (1991). This changed the normal sequence at the splice junction from CAGAGGTCA, of which the first CAG is an intronic sequence, to CAGGTCA. Groden et al. (1991) noted that although this deletion is within the 5-prime splice site, known consensus sequences suggest that the splice site may still be maintained. The deletion would therefore result in a frameshift and premature stop codon. Studies of both parents showed that the mutation in the proband was de novo; however, it had been transmitted to 2 of his 3 children.
In a patient with familial adenomatous polyposis-1 (175100), Groden et al. (1991) identified a heterozygous 904C-T transition in exon 8 of the APC gene, resulting in an arg-to-ter substitution.
In a patient with familial adenomatous polyposis-1 (175100), Groden et al. (1991) identified a heterozygous 1-bp deletion in exon 10 of the APC gene, resulting in a frameshift and truncation of the protein within 30 bases.
In a patient with familial adenomatous polyposis-1 (175100), Groden et al. (1991) identified a heterozygous 1500T-G substitution in exon 11 of the APC gene, resulting in a tyr-to-ter substitution.
In a 24-year-old patient with Gardner syndrome (see 175100), Nishisho et al. (1991) identified a C-to-T transition in the APC gene, resulting in an arg414-to-cys (R414C) substitution. The patient had adenomatous polyposis and a mandibular osteoma.
In 2 unrelated patients, a 46-year-old with FAP1 (175100) and a 27-year-old with Gardner syndrome manifest as polyposis with a desmoid tumor, Nishisho et al. (1991) identified a C-to-T transition in the APC gene, resulting in an arg302-to-ter (R302X) substitution. There was cosegregation of the mutation with the disease phenotype in multiple members of the FAP kindred. The findings suggested that the specific mutation does not completely specify the extracolonic manifestations of FAP, and that the phenotype is likely to be the result of other genetic or environmental influences.
Chung et al. (2006) identified a de novo R302X mutation in a 19-year-old woman with Gardner syndrome (see 175100) manifest as the cribriform-morular variant of papillary thyroid carcinoma, which had been discovered 8 months before the discovery of polyposis of the colon.
In a 39-year-old patient with Gardner syndrome (see 175100), Nishisho et al. (1991) found a C-to-G transversion in the APC gene, resulting in a ser280-to-ter (S280X) substitution. The patient had polyposis and a mandibular osteoma.
In a patient with Gardner syndrome (see 175100), Nishisho et al. (1991) identified a heterozygous C-to-G transversion in the APC gene, resulting in a ser713-to-ter (S713X) substitution. The patient had polyposis and a mandibular osteoma.
In a colorectal cancer (see 114500) cell line, Nishisho et al. (1991) identified a somatic C-to-T transition in the APC gene, resulting in a gln1338-to-ter (Q1338X) substitution. Study of tissues from the patient from whose tumor the cell line was established 28 years earlier showed that the mutation was in the primary tumor and in metastases but not in normal tissues.
In gastric cancer tumor tissue (see 613659), Horii et al. (1992) identified a somatic G-to-A transition in the APC gene, resulting in a gly1120-to-glu (G1120E) substitution.
In gastric cancer tumor tissue (see 613659), Horii et al. (1992) identified a somatic C-to-T transition in the APC gene, resulting in a gln1067-to-ter (Q1067X) substitution.
In 2 apparently unrelated Dutch patients with FAP1 (175100), Fodde et al. (1992) identified a 4-bp deletion (ATAG) in codons 169-171 of the APC gene, resulting in a frameshift and premature termination. The wildtype sequence suggested the presence of a head-to-tail duplication of a tetranucleotide which offered a suitable substrate for unequal but homologous crossover events leading to either triplication or deletion of the 4-bp unit. Haplotype analysis performed with intragenic and flanking polymorphic markers indicated that the 2 identical 4-bp deletions were located on different chromosomes, suggesting that they had arisen independently.
In affected members of a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a 1-bp insertion (A) at codon 357 of the APC gene, resulting in a premature termination codon 22 bp downstream.
In affected members of a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a C-to-T transition in the APC gene, resulting in a gln541-to-ter (Q541X) substitution.
Hamilton et al. (1995) found the same mutation in an FAP family in which 1 patient also had a calcified ependymoma, indicating brain tumor-polyposis syndrome-2.
In a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a C-to-T transition in the APC gene, resulting in an arg554-to-ter (R554X) substitution.
In a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a C-to-T transition in the APC gene, resulting in an arg564-to-ter (R564X) substitution.
In a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a 1-bp insertion (A) in codon 629 of the APC gene, resulting in a premature stop codon 13 bp downstream.
In a Dutch family with FAP1 (175100), Fodde et al. (1992) identified a C-to-A transversion in the APC gene, resulting in a tyr935-to-ter (Y935X) substitution.
In tumor tissue from a periampullary adenoma from a patient with FAP (175100), Bapat et al. (1993) identified a somatic 2-bp deletion (AG) at codon 1465 of the APC gene. The patient had a germline APC mutation (611731.0023).
Martin-Denavit et al. (2001) described the 1465delAG mutation in 2 unrelated families with Gardner syndrome who showed interfamilial phenotypic heterogeneity. The mutation was identified by a simple nonradioactive method using a heteroduplex analysis and specifically characterized by sequence analysis. In both families, fibromatosis was noted before polyposis, leading to the diagnosis of Gardner syndrome. In the first family, progression of fibromas and osteomas was much greater, and colonic polyposis was sparser, compared to the second family. Prognosis was mainly based on the dramatic evolution of the desmoid tumors before the age of 30. In contrast, desmoid manifestations remained discrete in family 2, and the prognosis was dependent on the development of colon cancer. The wide inter- and intrafamilial variability of the phenotype suggested the operation of one or more modifier genes. Since a 'second hit' is thought to be necessary for the development of desmoid tumors, this may account for a difference between and even within families; a modifier locus may have favored a 'second hit' in mesenchymal cells in family 1, and in colonic epithelial cells in family 2.
In tumor tissue of a periampullary adenoma from a patient with FAP (175100), Bapat et al. (1993) identified a somatic 4-bp deletion (AGAG) at codon 1464 of the APC gene. The patient had a germline APC mutation (611731.0023).
In 1 of 7 families with what Spirio et al. (1993) referred to as an 'attenuated' form of familial polyposis (see 175100), the authors identified a 470G-A transition in exon 4 of the APC gene, resulting in a trp157-to-ter (W157X) substitution, predicted to generate a truncated product of 156 amino acids. This mutation was present in all affected family members, as well as in 3 asymptomatic individuals. Notably, one of the latter had reached the age of 41 without developing any clinically detectable adenomatous polyps. This mutation and 3 others detected in other atypical families were located very close to one another and nearer the 5-prime end of the APC gene than any base substitution or small deletion previously discovered in patients with classic APC.
In affected members of a family with FAP1 (175100), Hamilton et al. (1995) identified a C-to-T transition in the APC gene, resulting in a gln215-to-ter (Q215X) substitution. One patient developed an anaplastic astrocytoma at age 37, indicating brain tumor-polyposis syndrome-2 (see 175100).
In 9 patients with severe FAP1 (175100), Gayther et al. (1994) identified a 5-bp deletion at codon 1309 of the APC gene. The 5-bp deletion extends from the last base of codon 1309 to the first base of codon 1311; some refer to it as the 'codon 1309' APC mutation. This mutation may account for 9% of FAP due to mutations in the APC gene. The mutation tends to be associated with more severe and earlier onset disease and the presence of congenital hypertrophy of the retinal pigmented epithelium (CHRPE).
Bapat et al. (1993) identified a 5-bp deletion at codon 1309 in an FAP patient with periampullary adenomas. Two different somatic mutations in the APC gene (611731.0019; 611731.0020) were identified in 2 distinct adenomas from this patient.
Distante et al. (1996) described a 5-year-old girl with the mutation who presented with rectal bleeding from extensive polyposis of the colon; her father had had a colectomy for FAP at the age 23.
Shaoul et al. (1999) described a 6-year-old boy with FAP and congenital cholesteatoma (see 604183). They suggested that cholesteatoma represents a tumor-like lesion with biologic characteristics resembling other alimentary lesions of FAP. The patient first came to medical attention at the age of 4 years because of intermittent painless hematochezia. Colonoscopy at the age of 6 years showed multiple polyps of the colon. Eye examination showed hyperpigmented retinal lesions in the temporal retina of each eye, but radiographic studies of the mandible and maxilla showed no changes. The cholesteatoma was detected at the age of 4 years because of unilateral conductive hearing loss. Polyps had been detected in the patient's mother at the age of 25 years and a subtotal colectomy was performed. In both the mother and the child, DNA analysis identified a 5-bp deletion (GAAAG) at codons 1309-1311 in exon 15 of the APC gene. Shaoul et al. (1999) commented that mutations at codon 1309 have been associated with early development of adenomatous polyps and a greater risk of malignancies at an early age. Furthermore, the same mutations are strongly associated with the presence of congenital hypertrophy of the retinal pigment epithelium.
In tumor tissue isolated from hepatoblastoma (see 114550) of 3 unrelated affected Japanese boys, Oda et al. (1996) identified an A-to-T transversion in the APC gene, resulting in a ser1395-to-cys (S1395C) substitution. Oda et al. (1996) noted that hepatoblastoma is an extracolonic feature of FAP (175100).
In affected members of a family with hereditary desmoid disease (DESMD; 135290), Eccles et al. (1996) identified a heterozygous 2-bp insertion (AA) at codon 1924 of the APC gene, resulting in a frameshift and premature protein termination. The mutation occurred in the 3-prime end of exon 15.
Scott et al. (1996) identified a germline heterozygous APC mutation in the original kindred with hereditary desmoid disease (DESMD; 135290) described by Maher et al. (1992). Direct sequencing of genomic DNA revealed a 4-bp deletion at nucleotides 5844-5847 (codon 1962) of the APC sequence. The same mutation occurred in 2 other apparently unrelated families with desmoid tumors. Haplotype analysis suggested a common origin for the APC mutation in the 3 families.
In affected members of a large family with FAP1 (175100), Scott et al. (1995) identified a 1-bp deletion (5960delA) in codon 1987 of the APC gene, resulting in a frameshift and premature termination 61 codons downstream. The mutation was in the 3-prime end of exon 15 in the 3-prime region of the APC gene. Affected family members showed a highly variable phenotype, with both severe disease with extracolonic manifestations and mild disease.
Van der Luijt et al. (1996) did not detect a truncated APC protein in cells from the family reported by Scott et al. (1995).
In a large Dutch family with attenuated FAP1 (see 175100), van der Luijt et al. (1996) identified a 4-bp (TTCT) deletion at codons 1860 to 1862 of the APC gene, resulting in a frameshift and an immediate stop codon. The deletion occurred in the 3-prime part of exon 15 and did not result in a stable truncated protein; only the wildtype APC protein was detected in an affected individual. The phenotype in this family showed marked variability in number of polyps (ranging from 0 to more than 100) and relatively late age at cancer onset (mean 56 years). None of the patients had desmoid tumors. Van der Luijt et al. (1996) hypothesized that the milder phenotype in this family was due to haploinsufficiency of a normal APC protein and absence of a truncated APC protein with a possible dominant-negative effect.
In a 39-year-old Ashkenazi Jewish man with colorectal adenomas and a family history of colon cancer (175100), Laken et al. (1997) identified a 3920T-A transversion in the APC gene, resulting in an ile1307-to-lys (I1307K) substitution. An in vitro synthesized protein assay from this allele showed a truncated APC protein. The T-to-A change converted an AAATAAAA sequence to (A)8 and was postulated to result in failure of the cellular transcriptional or translational machinery, resulting in a truncated protein. The (A)8 tract not only was unstable in vivo, leading to somatic mutation, but also appeared to be unstable in vitro during the enzymatic manipulations employed in the IVSP assay. The same mutation was identified in 28% of Ashkenazi Jews with a family history of CRC and in the carrier state of 6% unaffected Ashkenazim from the general population. Analysis of tumor tissue occurring in CRC patients with the I1307K mutation revealed that nearly half contained somatic truncating mutations closely surrounding the germline mutation; all the somatic mutations occurred exclusively in the I1307K allele. Laken et al. (1997) concluded that presence of the I1307K mutation results in a 2-fold increased risk for colorectal cancer, although the change in itself does not likely contribute to the disease.
Petersen et al. (1998) addressed the increasingly important problem of interpreting the significance of missense mutations found in disease-causing genes, citing the APC I1307K mutation as a case in point. Using a Bayesian approach that incorporated genetic information on affected relatives, relationship of the relatives to the proband, the population frequency of the mutation, and the phenocopy rate of the disease, the authors concluded that the I1307K mutation was likely to be disease causing. Petersen et al. (1998) also developed a simple approximation for rare alleles and considered the case of unknown penetrance and allele frequency.
By genotyping 5,081 Ashkenazi volunteers in a community survey, Woodage et al. (1998) concluded that APC I1307K carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage et al. (1998) emphasized that the large majority of I1307K carriers would not develop cancer of the colon or breast, and that only a small proportion of Jewish individuals who develop these cancers will be carriers. Redston et al. (1998) identified a heterozygous I1307K polymorphism in 66 (10.4%) of 632 unrelated Ashkenazi Jewish women with primary invasive breast cancer (113705). This proportion was significantly greater than the 7.03% carrier frequency observed in the study by Woodage et al. (1998). However, prevalence data suggested that the effect of the I1307K allele on breast cancer risk was largely or entirely limited to those with BRCA (see, e.g., BRCA1, 113705) founder mutations. Redston et al. (1998) concluded that the I1307K polymorphism emerges as a candidate low-penetrance breast cancer susceptibility allele or a genetic modifier of risk in BRCA heterozygotes.
Frayling et al. (1998) identified the I1307K allele in 3 patients of Ashkenazi Jewish descent with multiple colorectal adenomas and/or carcinoma.
Yuan et al. (1998) described a French Canadian kindred in which HNPCC was related to a novel truncating mutation in the MLH1 gene (120436.0009). In the same family, they found the I1307K APC polymorphism, which had previously been identified only in individuals of self-reported Ashkenazi Jewish origin. However, there appeared to be no relationship between the I1307K polymorphism and the presence or absence of cancer in the French Canadian family.
Gryfe et al. (1999) identified the APC I1307K allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC I1307K allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P equal to 0.01). Compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Gryfe et al. (1999) estimated that the APC I1307K polymorphism directly contributes to 3 to 4% of all Ashkenazi Jewish colorectal cancer.
In persons at average risk for colorectal cancer, Rozen et al. (1999) identified the APC I1307K variant in 5.0% of 120 European and 1.6% of 188 non-European Jews (P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer (P = 0.02), and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred individually or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia.
Prior et al. (1999) did not identify the I1307K mutation among 345 non-Ashkenazim individuals with colorectal cancer, suggesting that it is restricted to that population. Somatic mutations occurred at a lower frequency and were more randomly distributed when the I1307K allele was not present.
In an editorial, Gruber et al. (1999) compared the group of Prior et al. (1999) to investigators at the scene of an accident. Prior et al. (1999) carefully characterized the somatic mutations associated with the I1307K polymorphism as if they were crash sites near this hypermutability oil slick. Tumors with the wildtype allele at codon 1307 had a variety of somatic mutations that were distributed randomly in the APC gene and were not tightly clustered around the 1307 codon. These results contrasted sharply with previous crash site investigations of the mutant allele which showed characteristic mutations piling up like cars around the oil slick. This earlier work by the Vogelstein group (Laken et al., 1997), confirmed by Gryfe et al. (1998), showed that mutations arising in association with the mutant allele appeared to be localized to a 29-bp region around the gene and were almost always insertions. Furthermore, these unusual somatic mutations were restricted to the mutant allele, never occurring in the wildtype allele in the same patients. The reference to 'crash sites' and 'oil slick' provided useful imagery comparable to the 'gatekeeper' and 'caretaker' roles of other cancer-related genes--again products of the Vogelstein laboratory, as is the designation 'landscaper,' envisioned as the basis of colorectal cancer in juvenile polyposis.
Patael et al. (1999) found the I1307K polymorphism in 2 non-Ashkenazi Jewish women in Israel and hypothesized that among Jewish persons it may not be restricted to Ashkenazim, but may actually reflect a common ancestral polymorphism. The haplotype pattern in these 2 women and in 9 Ashkenazi carrier controls was identical in all individuals regardless of ethnic origin.
Lamlum et al. (2000) screened 164 unrelated patients with multiple (3-100) colorectal adenomas for germline variants throughout the APC gene, and found 3 Ashkenazi patients harboring the I1307K mutation. Germline APC variants accounted for approximately 10% of all patients with multiple adenomas. The authors recommended screening multiple adenoma patients of Ashkenazi descent for the I1307K variant.
Silverberg et al. (2001) found no increased frequency of I1307K in Ashkenazi Jewish patients with inflammatory bowel disease and concluded that this mutation cannot account for the increased susceptibility to colorectal cancer associated with inflammatory bowel disease.
Rozen et al. (2002) reported studies in Israel indicating that I1307K is a low-penetrance variant with a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. They concluded that I1307K is a founder variant in Jews of different ethnic origin, mainly Ashkenazim, and it explains only partially their higher incidence of colorectal carcinoma.
Lynch and de la Chapelle (2003) schematized the somatic mutations that occur in carriers of the I1307K polymorphism, which results in a stretch of 8 adenosines that is believed to increase the risk of somatic mutations as a result of slippage during replication. Lynch and de la Chapelle (2003) illustrated the types of somatic changes in colonic tumors, e.g., an addition of 1 adenosine seen in the affected allele of many carriers. The addition or loss of a nucleotide causes a frameshift and loss of function of APC, constituting an important somatic event in tumor initiation.
In individuals of Ashkenazi, Sephardi, and Arab descent, Niell et al. (2003) found a common progenitor haplotype spanning across APC I1037K from the centromeric marker D5S135 to the telomeric marker D5S346. The ancestor of modern I1307K alleles existed 87.9 to 118 generations ago (approximately 2,200 to 2,950 years ago). This estimate indicated that I1307K existed at about the time of the beginning of the Jewish diaspora, explaining its presence in non-Ashkenazi populations. The data did not indicate that selection operated at I1307K, providing compelling evidence that the high frequency of disease-susceptibility alleles in the Ashkenazim is due to genetic drift, not selection.
In 2 previously reported patients with severe Gardner phenotype (see 175100) (Davies et al., 1995), Armstrong et al. (1997) identified a 2-bp deletion (1538delAG) in the APC gene, resulting in a frameshift and premature termination. The patients were of different ethnic backgrounds and had different haplotypes, suggesting that the same mutation had arisen in 2 separate populations.
In affected members of 2 unrelated families with Gardner syndrome (see 175100), Eccles et al. (1997) identified a C-to-T transition in exon 11 of the APC gene, resulting in an arg499-to-ter (R499X) substitution. The proband was diagnosed with FAP at age 7 years and colon cancer at age 9 years. Multiple family members had FAP, colon cancer, and extracolonic features, including CHRPE, osteomas, and sebaceous cysts.
In affected members of a family with FAP1 (175100), Eccles et al. (1997) identified a C-to-T transition in exon 11 of the APC gene, resulting in a tyr486-to-ter (Y486X) substitution. The proband was diagnosed with FAP at age 15 years and had a colectomy the same year. Three other affected family members had colectomies at ages 9 and 15 years.
In affected members of a family with FAP1 (175100), Cama et al. (1994) identified a 3-bp deletion in the APC gene: 2 adenine residues of codon 437 and the adjacent guanine residue at the consensus donor splicing sequence of exon 9. The sequence of the 3-prime end of exon 9 was converted from CCA A/gtat to CC/tat. The APC gene mutation abolished the donor site of exon 9a, used in both alternatively spliced isoforms of the exon. The phenotype was characterized by hundreds of colorectal adenomas (320 to more than 500); a child in this family already had 460 adenomas at the age of 8 years. Analysis of the relative levels of mutant and wildtype transcripts in unaffected colonic mucosa demonstrated that the mutant allele was not expressed. In contrast, a second kindred with a neighboring mutation (611731.0034) in exon 9 in the portion of the exon that is alternatively spliced showed an attenuated form of FAP characterized by a low number of colorectal adenomas. The model suggested by these 2 kindreds suggested that the type of mutation and transcript dosage effects contribute to the heterogeneity of disease phenotypes in FAP.
In a family with an attenuated form of FAP1 (see 175100) characterized by a low number of colorectal adenomas (up to 22), Curia et al. (1998) identified a 2-bp deletion within codon 367 of exon 9 of the APC gene. This frameshift mutation was located in the portion of exon 9 that undergoes alternative splicing and was predicted to introduce a premature termination signal at codon 376 in the fraction of mature transcripts containing the alternatively spliced form of exon 9. Thus, splicing-out of the mutation site into a fraction of mRNA molecules was predicted, with the residual production of wildtype transcripts from the mutant APC alleles. Curia et al. (1998) contrasted this finding with that in a neighboring exon 9 mutation (611731.0033) that led to deletion of exon 9 and was associated with a severe FAP phenotype characterized by hundreds of colorectal adenomas. They suggested that, in addition to the mutation site, the type of mutation and transcript dosage effects contribute to the heterogeneity of disease phenotypes in FAP.
In a family with attenuated FAP of variable phenotype (see 175100), Young et al. (1998) identified a 2-bp deletion in the alternatively spliced region of exon 9 at codon 398, resulting in a frameshift and stop signal 4 codons downstream. The clinical features ranged from sparse right-sided polyposis and cancer in the proximal colon at the age of 34 to pancolonic polyposis and cancer at the age of 68. Rectal sparing was common to all affected members. Alternatively spliced transcripts that deleted the mutation were readily amplified from normal colonic mucosa, providing an explanation for the attenuated phenotype seen in this family.
In 4 patients with multiple colorectal adenomas and/or carcinomas (see 175100), Frayling et al. (1998) identified a 3949G-C transversion in exon 15 of the APC gene, resulting in a glu1317-to-gln (E1317Q) substitution. One of these individuals had an unusually large number of metaplastic polyps of the colorectum. Although 2 patients had a remote family history of colorectal cancer and 1 had a family history of gastric cancer, none had a family history of colonic adenomas or classic FAP.
Lamlum et al. (2000) identified the E1317Q variant in 7 of 164 unrelated patients with multiple (3-100) colorectal adenomas. Among the entire group, germline APC variants accounted for approximately 10% of patients with multiple adenomas. The authors recommended screening multiple adenoma patients for a restricted number of germline APC variants, including E1317Q.
In a 57-year-old man with FAP1 (175100), Kartheuser et al. (1999) identified a 1-bp deletion (5960delA) in the 3-prime end of exon 15 of the APC gene, resulting in a frameshift and premature termination. The patient had an unusual and complex phenotype with colorectal, gastric, and periampullary adenomatous polyposis, as well as 3 bilateral adrenocortical adenomas. His mother died of colon cancer at age 66. Three of the patient's 4 asymptomatic children were also found to have the mutation.
In a family with an attenuated form of adenomatous polyposis coli (see 175100) and thyroid cancer, Soravia et al. (1999) identified a germline 2-bp deletion (937delGA) in exon 9 of the APC gene, resulting in a frameshift and a premature stop codon. The thyroid tumors showed a range of morphologic features: some exhibited typical papillary architecture and were associated with multifocal carcinoma; in others, there were unusual areas of cribriform morphology, and spindle-cell components with whorled architecture. RET/PTC1 and RET/PTC3 (see 164761) were expressed in thyroid cancers.
In affected members of a family with Gardner syndrome (see 175100) and thyroid cancer, Soravia et al. (1999) identified a heterozygous 2092T-G transversion in exon 698 of the APC gene, resulting in a leu698-to-ter (L698X) substitution. The thyroid tumors showed a range of morphologic features: some exhibited typical papillary architecture and were associated with multifocal carcinoma; in others, there were unusual areas of cribriform morphology, and spindle-cell components with whorled architecture. Affected members showed classic FAP associated, in addition to thyroid carcinoma, with desmoid tumor, duodenal polyposis, osteoma, dental abnormalities, and epidermoid cysts. RET/PTC1 and RET/PTC3 (see 164761) were expressed in thyroid cancers.
In affected members of an Amish family with autosomal dominant inheritance of desmoid tumors (DESMD; 135290), Halling et al. (1999) identified a 337-bp insertion in an AluI sequence at codon 1526 of the APC gene, resulting in protein truncation. The presence of a poly(A) tail at the 3-prime end of the insertion suggested that the AluI sequence was inserted by a retrotranspositional event.
Pilarski et al. (1999) reported a 39-year-old man with attenuated FAP1 (see 175100) and a cytogenetically visible interstitial 5q deletion. Fluorescence in situ hybridization analysis with 2 cosmid probes specific for the 5-prime and 3-prime ends of the APC gene indicated that the entire locus was deleted. The number of polyps (50-60) seen in this patient was consistent with attenuated FAP. Pilarski et al. (1999) stated that this was the first reported case of attenuated FAP associated with a germline deletion of the entire APC gene.
In 5 separately ascertained families from Newfoundland with attenuated FAP1 (see 175100), Spirio et al. (1999) identified a G-to-A transition in the splice acceptor site of intron 3 of the APC gene, which created a mutant RNA without exon 4 of APC. The observation of the same APC mutation in 5 families from the same geographic area suggested a founder effect. The identification of this germline mutation strengthened the correlation between the 5-prime location of an APC disease-causing mutation and the attenuated polyposis phenotype.
Rozen et al. (1999) reported a large kindred in which a novel 11-bp insertion (AAGGATGATAT) at nucleotide position 1060 (codon 353) in exon 9 of the APC gene segregated with classic FAP with or without colorectal cancer (175100). In at least 5 mutation carriers, however, there were no clinical, endoscopic, or histologic features of FAP at the time of the study. The authors commented that this family highlighted the possible contribution of low penetrance germline APC mutations to 'sporadic' colorectal neoplasia.
In affected members of a large French Canadian kindred with hereditary desmoid disease (DESMD; 135290), Couture et al. (2000) identified a heterozygous 4-bp deletion (7929delTCTA) at codons 2643-2644 of the APC gene, resulting in a frameshift and premature termination. The mutant APC allele did not express a stable truncated protein in vivo. The phenotype was characterized by the early onset of multiple tumors, arising near the axial skeleton and in proximal extremities. Although penetrance of desmoid tumors was nearly 100%, expression of the disease was variable. Many gene carriers had cutaneous cysts. Polyposis of the colon was rarely observed in the affected individuals and no upper gastrointestinal polyps were documented. In a desmoid tumor from the proband, Couture et al. (2000) identified a somatic 1-bp deletion (3720delT; 611731.0046) in codon 1240 of the APC gene.
Couture et al. (2000) identified a somatic 1-bp deletion (3720delT) in codon 1240 of the APC gene in desmoid tumor tissue from a patient with hereditary desmoid disease (DESMD; 135290) and a germline mutation in the APC gene (611731.0045). Immunohistochemistry on the tumor tissue demonstrated elevated levels of beta-catenin (116806).
In a man with Gardner syndrome (see 175100) reported by Dhaliwal et al. (1990), Su et al. (2001) identified a gln208-to-ter (Q208X) mutation in the APC gene. The patient's 28-year-old son was diagnosed with FAP at age 15 and underwent proctocolectomy at the age of 23. The son also developed multiple intraperitoneal desmoid tumors and a hepatocellular carcinoma. In the liver tumor of the son, Su et al. (2001) showed that the wildtype allele of the APC gene carried a somatic 1-bp deletion at codon 568 (611731.0048). The somatic APC mutation was not found in the surrounding normal tissue.
In a hepatocellular tumor (114550) of a patient with Gardner syndrome (see 175100 and 611731.0047), Su et al. (2001) identified a somatic 1-bp deletion at codon 568 of the APC gene. The somatic APC mutation was not found in the surrounding normal tissue.
In a proband who had a phenotype consistent with attenuated FAP1 (see 175100), Su et al. (2002) found a genomic rearrangement resulting in a 56-kb deletion and consequent removal of the entire exon 15 of the APC gene. This rearrangement also resulted in a hybrid gene between APC and U2AF1RS1 (601079).
In a family with features of classic FAP1 (175100), Su et al. (2002) detected a genomic rearrangement resulting in a 73-kb deletion and consequent removal of the entire exon 15 of the APC gene.
In the Spanish Balearic Islands, Gonzalez et al. (2005) found that a 5-bp deletion (3221_3225delACAAA) at codon 1061 of the APC gene was the most common basis for FAP1 (175100). Haplotype analysis of 5 families was consistent with a founder effect.
This variant is classified as a variant of unknown significance because its contribution to Cenani-Lenz syndrome (CLSS; 212780) has not been confirmed.
Patel et al. (2015) described an extended consanguineous Saudi family with typical features of CLSS in addition to significant scoliosis. Four affected members of the family (3 sibs and their first cousin) had an identical combination of 4-limb syndactyly, scoliosis, and mild facial dysmorphism, including broad forehead, hypertelorism, depressed nasal bridge, and prominent upper incisors. Height and development were normal in all 4 affected family members. The disorder mapped to a single autozygous interval on chromosome 5q22.2. Whole-exome sequencing in this interval revealed the presence of a novel splicing mutation in APC, a 3-bp deletion upstream of exon 5 (c.423-5_423-3delAAT, NM_000038.5) that was predicted to abolish the canonical acceptor site. The mutation, which was found in homozygosity in all affected members, fully segregated with the disorder in the family and was not detected in the 1000 Genomes Project and Exome Sequencing Project databases or in 549 ethnically matched exomes. RT-PCR confirmed abnormal splicing in the patients, who showed a doublet band representing the normal transcript as well as an aberrant transcript in which exon 5 was completely skipped, resulting in frameshift and introduction of a premature stop codon (p.Arg141SerfsTer8). Because the band corresponding to the normal transcript was consistently weaker in intensity, Patel et al. (2015) quantified the reduction by real-time RT-PCR, which demonstrated an approximately 80% reduction compared with normal controls. Global gene expression profiling detected upregulation of WNT (164820)/beta-catenin (CTNNB1; 116806) signaling. The authors speculated that, similar to how LRP4 (604270) mutations are predicted to negate the protein's antagonistic effect on WNT/beta-catenin signaling, reduction of APC may increase the availability of beta-catenin by virtue of impaired degradation, leading to a similar phenotypic outcome.
In 28 affected members of a large 5-generation Australian family (family 1) segregating autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), originally described by Worthley et al. (2012) as family 1, Li et al. (2016) identified heterozygosity for a c.-195A-C transversion (c.-195A-C, NM_001127511) and a 1-bp deletion (c.-125delA, NM_001127511), located in cis within the APC promoter 1B. The mutations were also detected in 4 unaffected family members, including 3 obligate carriers, but were not found in 2,326 Australian controls, in 344 germline samples from an in-house WGS cancer project, or in the 1000 Genomes Project database. By electrophoretic mobility shift assay (EMSA), Li et al. (2016) demonstrated that the c.-195A-C mutation disrupts binding to the promoter 1B region in both AGS and RKO cells. In luciferase reporter assays, constructs with c.-195A-C plus c.-125delA, or c.-195A-C alone, showed significantly decreased activity compared to wildtype. In addition, the construct containing both c.-195A-C and c.-125delA showed reduced expression in the HCT116 colorectal cancer cell line. The c.-125delA variant alone only showed significantly decreased activity in RKO and HCT116 cells. Two family members with typical proximal polyposis of the stomach died from intestinal-type gastric adenocarcinoma at ages 33 and 48 years with hepatic metastases. Colonoscopy results were available from 13 affected family members, none of whom had colorectal polyposis; the most advanced colorectal pathology involved 8 simple tubular adenomas removed over 4 colonoscopies and there was no family history of colorectal cancer.
In 4 families (2, 4, 5, and 6) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), 1 of which was the US family originally described by Worthley et al. (2012) as family 2, Li et al. (2016) identified heterozygosity for a c.-191T-C transition (c.-191T-C, NM_001127511) in a YY1 binding motif of the APC promoter 1B that segregated with disease in all 4 families and was not found in 344 germline samples from an in-house WGS cancer project or in the 1000 Genomes Project database. By EMSA, Li et al. (2016) demonstrated that the c.-191T-C mutation disrupts binding to the promoter 1B region in both AGS and RKO cells. In luciferase reporter assays, constructs with c.-191T-C showed significantly decreased activity compared to wildtype.
In a father and 3 daughters from a 3-generation Czech family with GAPPS, Repak et al. (2016) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA analysis was not reported for the paternal grandmother who also had proximal gastric polyposis and died of gastric cancer at age 49 years.
In a 38-year-old Austrian woman with GAPPS, Beer et al. (2017) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA was unavailable from her father, who died of gastric cancer at age 57 years.
In 24 individuals from 8 Czech families with GAPPS, Foretova et al. (2019) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. Of the 24 mutation carriers, 20 had massive gastric polyposis; in addition, 1 female carrier had incipient polyposis at age 58 years, 2 female carriers did not have polyposis of the stomach at ages 31 and 65, and a 92-year-old asymptomatic male carrier did not undergo gastroscopy due to his advanced age.
In affected members of 2 multiplex Japanese families with GAPPS, Kanemitsu et al. (2021) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In 2 affected sibs from a Canadian family (family 3) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), originally described by Worthley et al. (2012) as family 3, Li et al. (2016) identified heterozygosity for a c.-192A-G transition (c.-192A-G, NM_001127511) in the APC promoter 1B. The mutation was not present in a sib with fewer than 30 fundic gland polyps, and was not found in 344 germline samples from an in-house WGS cancer project or in the 1000 Genomes Project database. By EMSA, Li et al. (2016) demonstrated that the c.-192A-G mutation disrupts binding to the promoter 1B region in both AGS and RKO cells. In luciferase reporter assays, constructs with c.-192A-G showed significantly decreased activity compared to wildtype.
In affected members of 8 families from the same region of France with familial adenomatous polyposis-1 (FAP1; 175100), Lagarde et al. (2010) identified heterozygosity for a g.20377206A-T transversion in the APC promoter 1B. Li et al. (2016) stated that using more recent nomenclature, this mutation would be designated c.-192A-T (c.-192A-T, NM001127511). They noted that although fundic gland polyps (FGPs) were prominent in the French families, all probands and many family members had undergone colectomy for florid colonic polyposis. By EMSA, Li et al. (2016) demonstrated that the c.-192A-T mutation disrupts binding to the promoter 1B region in both AGS and RKO cells.
In 5 affected individuals over 3 generations of a family with profuse fundic gland polyps as well as colorectal polyposis (FAP1; 175100), Li et al. (2016) identified heterozygosity for a c.-190G-A transition (c.-190G-A, NM_001127511) in a YY1 binding motif in the APC promoter 1B. The mutation was not found in 2 unaffected family members. By EMSA, Li et al. (2016) demonstrated that the c.-190G-A mutation disrupts binding to the promoter 1B region in both AGS and RKO cells.
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