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.
In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those > or =55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively).
Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas.
These results suggest that the inactivation of the APC gene is very common in sporadic colorectal cancer, and the main inactivation mechanism of the APC gene is promoter hypermethylation.
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.
Our results suggest that the COPPER plate DHPLC approach is a simple, cost effective, accurate, universal, and reproducible technology for screening hMLH1 and hMSH2 genes which are associated with human CRC.
This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes.
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.
To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O6-methylguanine DNA methyltransferase (MGMT) and Human Mut-L Homologue 1 (MLH1) promoter hypermethylation are associated with APC, KRAS and BRAF mutations among 734 CRC patients.
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).
In conclusion, we show that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the hMLH1 status) and MSS CRCs, may target distinct kinases within the RAS/RAF/MAPK pathway.
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.
Validation cohort: FFPE samples from 154 patients with primary stage III CRC (originally included in the RANX05 study) were classified according to MMR status by immunohistochemical analysis using validated antibodies for MLH1, MLH2, MSH6 and PMS2, and information on TOP1, CEN20, TOP2A and CEN17 status was previously published for this cohort.
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.