Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women.
Based on recent estimates that 11.7-16.6 % of women with ovarian cancer are BRCA carriers and 2 % are HNPCC carriers, results suggest under-identification of carriers and under-utilization of genetic services by providers and patients.
Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations.
Studies examining MSI, loss of MMR gene expression by IHC staining and MLH1 promoter hypermethylation in ovarian cancer were identified by a systematic literature search of the PubMed electronic database through August 31, 2009.
Our results indicate that promoter hypermethylation is an important mechanism for loss of hMLH1 and hMSH2 expression in human ovarian cancer and may be a potential prognostic factor in ovarian cancer.
Serial 5'-deletion studies of the hMLH1 promoter region in ovarian cancer cells localized transcriptional enhancers to a region (-250 to -151 bp) that excludes the previously identified CCAAT element (-282) active in HeLa cells.
We studied the correlation between loss of hMLH1 expression in tumour cells and clinical outcome in 38 patients with ovarian cancer, who underwent cisplatin-based chemotherapy.
1) Coding DNA instability is likely to be a very rare event in OC and, therefore, may not significantly contribute to the development of OC, and 2) the high frequency of LOH at hMLH1 observed in our ovarian tumors suggests that further investigation is needed to determine if such a trend exists in other mismatch DNA repair and/or critical genes.
This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.
The fact that we found no germline pathologic mutations in hMSH2 and hMLH1 (predominant sites of mutation in HNPCC) in MIN+ OC cases, suggests that the genetic basis of MIN in OC can be different from that in HNPCC; our finding that distinct microsatellite banding patterns largely distinguish sporadic from familial OC, may reflect the involvement of different DNA repair genes in MIN in individual OC cases.
Amongst the important known susceptibility genes are those dominant genes conferring a high risk of breast and ovarian cancer (BRCA1), colon cancer (hMSH2 and hMLH1), and melanoma (MLM).