One colorectal cancer cell line contained deletions in both alleles of the putative mismatch repair gene hMSH2, and one endometrial cancer cell line contained a 4-base pair duplication in one hMSH2 allele.
The risk of endometrial cancer in the entire group of EPCAM deletion carriers is significantly lower than that in MSH2 mutation carriers, but the actual risk appears to be dependent on the size and location of the EPCAM deletion.
In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers.
Genetic counseling and testing for the MSH2A636P mutation is indicated for Ashkenazi Jewish women with an endometrial cancer, especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer.
CRC and endometrial carcinoma were associated with a greater probability of detecting pathogenic mutations in mismatch repair genes, with MSH2 involvement predominating.
The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype.
Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.
In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation.
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.
EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer.
No disease-causing mutation within the coding sequences of the hMLH1/hMSH2 and PTEN genes was found in patients with EC who had the mutator phenotype (MSI positive and IHC negative), except for a newly described hMLH1 missense mutation, Ile655Val, that was observed in 1 of 27 patients (4%).
DREMECELS was designed considering the malignancies with frequent alterations in DNA repair pathways, that is, colorectal and endometrial cancers, associated with Lynch syndrome (also known as HNPCC).
Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1.
Unselected Jewish women with EC who were diagnosed from January 1982 to January 2008 were genotyped for the predominant mutations in Jewish individuals in BRCA1 (185delAG, 5382InsC, Tyr978X) BRCA2 (6174delT), MSH2 (A636P, 324delCA) and MSH6 (c.3984_3987dup).
To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 genes.
We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up.
Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations.
The importance of the non-HNPCC genetic predisposition to endometrial cancer is unclear, and the familial aggregation of endometrial cancer after exclusion of HNPCC families may offer valuable clues about the involvement of non-HNPCC-related genes.
We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression.
HNPCC is an autosomal dominantly inherited cancer-susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age.