Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions.
Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern.
Consequently, we assessed the methylation status of CDKN2A/p16, MGMT, MLH1 and p14(ARF) in adenomas arising in the Lynch syndrome, a familial colon cancer syndrome caused by MLH1 and MSH2 mutations, to determine if DNA methylation is a "second hit" mechanism in CRC and to characterize the role of DNA methylation in the polyp phase of the Lynch syndrome.
We also tested whether other significant genetic or clinical status involved in CRC development, such as APC and TP53 mutations, MSI and TNM-Duke's staging, were related with the observed BRAF- or K-ras associated expression profiles.
This is the first genetic study of CRC in this region of the world to demonstrate the incidence of MSI, p16 methylation, and hMLH1 and MSH2 expression in the Omani population.
We suggest that the I1307K mutation may contribute to CRC in Israeli Arabs and that inactivating mutations of MSH2 and MLH1 may not be a major cause for early onset CRC.
The Val-carrying genotype was frequent in the studied population; however, it does not appear to exert any modifier effect on MLH1 or MSH2 pathogenic mutations and the development of colorectal cancer.
An APC gene sequence alteration, the I1307K allele, occurs in 6% of the Ashkenazi Jewish population and is reported to double the risk for colorectal cancer.
To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach.
Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH).
Value of pedigree/clinical data, immunohistochemistry and microsatellite instability analyses in reducing the cost of determining hMLH1 and hMSH2 gene mutations in patients with colorectal cancer.
Following official verification of family histories, 15 were thought to be in a low-risk category for developing colorectal cancer, 18 were moderate risk, 4 had a high-to-moderate risk and 2 satisfied the criteria for HNPCC.
Exome sequencing with focus on 14 genes related with hereditary colorectal cancer has shown a novel mutation in exon 19 of MLH1 gene (c.2133delC, p.Trp712Gly fs*71).
A novel MSH2 mutation is described in a Druze HNPCC family: a multigenerational family with 10 members in 4 generations affected with colorectal cancer (mean age of diagnosis 46.5 years), two with gastric cancer and one--endometrial cancer.
A total of 215 UK patients referred for genetic testing on the basis of a family history consistent with autosomal dominant hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) were tested by MLPA.