An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence.
Genetic alterations in the mutation cluster region of the APC gene occurred significantly more frequently in large adenomas and showed a trend towards an increase in villous adenomas and adenomas with moderate and severe dysplasia.
Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome.
For the APC gene, the incidence of LOH in the adenomas did not vary by histological type; the LOH status of the adenoma was associated with that of the paired carcinoma; but when both paired lesions had LOH of the APC gene, only 50% had LOH for the same allele.
The APC promoter is hypermethylated in 18% of primary sporadic colorectal carcinomas (n = 108) and adenoma (n = 48), and neoplasia with APC methylation fails to express the APC transcript.
Germ-line APC mutations were detected in each of three unrelated cases of TS, and additional (somatic) mutations were observed in colonic adenomas that had developed in one of these patients.
The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes.
We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas.
Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas.
DNA methylation was tested at Methylated IN Tumor (MINT) loci (1,2,12,31) and the CpG promoter region of genes MLH1, HPP1, MGMT, p14ARF and p16INK4a in FAP-associated adenomas (33) from 5 patients with a known APC mutation (Group 1, FAP), adenomas (29) from 4 Multiple Adenoma patients (Group 2 Multiple), adenomas (14) from 3 patients with sporadic colorectal cancers showing high microsatellite instability (Group 3, MSI-H) and adenomas (16) from 7 patients, with sporadic colorectal cancers showing microsatellite stable or low level instability (Group 4, MSS/MSI-L).
We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients.
We evaluated the cellular localization of beta-catenin in thyroid carcinomas associated (n = 4) or not associated (n = 173) with FAP, since loss of functional protein of the adenomatous polyposis coli (APC) gene leads to nuclear accumulation of beta-catenin in adenomas and carcinomas of the FAP colon.
These results suggest that inactivation of the APC gene by two mutations is involved in the development of moderate adenoma, and loss of heterozygosity of the APC gene is associated with further development to carcinoma.
Here, we have used MeDIP-seq to analyse the DNA methylome of APC(Min) adenoma as a model for intestinal cancer initiation, and we present a list of more than 13,000 recurring differentially methylated regions (DMRs) characterizing intestinal adenoma of the mouse.
Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes.
Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim.
Subsequent sequencing revealed a TTG to TAG mutation at codon 479 of APC, a GGT to GAT mutation at codon 12 of k-ras in both the adenoma and carcinoma, and a CGG to TGG mutation at codon 248 of p53 (exon 7) in the carcinoma.
We conclude that the APCI1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer.