hMLH1 Gene Mutations Research Articles

Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.

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

The aim of this study was to evaluate the significance of pedigree/clinical data, immunohistochemistry (IHC) and microsatellite instability (MI) analyses in the reduction of costs of constitutional hMLH1 and hMSH2 gene mutation diagnosis in patients with colorectal cancers (CRC). Pedigree/clinical data were evaluated on a series of 168 patients with CRC, including 43 consecutive sporadic late-onset and 25 consecutive, definitive or suspected hereditary non-polyposis colorectal cancer (HNPCC) cases, examined by IHC and MI analyses. In the latter group, 6/25 (24%) constitutional mutations were found. We detected no germline mutations in the sporadic late-onset patients. The lowest costs (880 Euro/mutation detected) were achieved by performing pedigree/clinical data (for exclusion of late-onset sporadic CRC) in conjuction with IHC only. In this model 1/6 (17%) mutations was missed. Additional preselection by IHC and MI analyses before sequencing was required to detect all mutations. In this approach, which seems to be the most effective in the search for hMLH1 and hMSH2 gene mutation, the cost was 1767 euro/mutation detected.

Public health perspectives on testing for colorectal cancer susceptibility genes

Context: About 131,600 new cases of colorectal cancer will be diagnosed in the United States in 1998. About 27,900 men and 28,600 women will die from colorectal cancer in 1998. Mutations to the hMSH2 gene on chromosome 2p and to the hMLH1 gene on chromosome 3p have been identified as causes of colorectal cancer. These mismatch repair genes, which have recently been cloned, account for most cases of hereditary nonpolyposis colorectal cancer (HNPCC), one of the most common cancer susceptibility syndromes known. The carrier frequency of hMSH2 and hMLH1 gene mutations in the U.S. population is unknown. An adenomatous polyposis coli (APC) gene variant (I1307K allele), which was recently reported in 1 in 17 Ashkenazi Jewish persons, may double the risk for colorectal cancer in that population. Conclusions: The use of genetic tests for susceptibility to cancer of the colon and other sites needs careful scrutiny. Several issues must be addressed before such tests can be recommended for population-based prevention programs. For example, the screening of population subgroups raises concern about potential discrimination and stigmatization. Before genetic tests for colorectal cancer are incorporated into future programs, the safety, effectiveness, and quality of these tests must be evaluated.

BRCA1, BRCA2, and Hereditary Nonpolyposis Colorectal Cancer Gene Mutations in an Unselected Ovarian Cancer Population

Rubin, Stephen C.; Blackwood, M. Anne; Bandera, Christina; Behbakht, Kian; Benjamin, Ivor; Rebbeck, Timothy R.; Boyd, Jeff Author Information

BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: Relationship to family history and implications for genetic testing

Objective: Our purpose was to determine the prevalence of BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in a large, unselected population of ovarian cancer patients and to evaluate the relationship between mutation status and a routinely obtained family history of cancer. Study Design: One hundred sixteen consecutive ovarian cancer patients seen for routine clinical care were examined for BRCA1, BRCA2, hMSH2, and hMLH1 gene mutations with use of the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct gene sequencing. Fisher's exact test was used to evaluate possible associations between BRCA1 and BRCA2 mutation status and specific familial characteristics. Results: Among 116 unselected ovarian cancer patients we identified a total of 13 germline mutations in 12 patients: 10 in BRCA1, one each in hMSH2 and hMLH1, and a single BRCA2 mutation, which occurred in a patient also carrying a BRCA1 mutation. More than half the patients with BRCA1 mutations had family histories that would generally be considered unremarkable. Of 22 family history variables analyzed, only two (maternal family history of breast or ovarian cancer, p = 0.037, and maternal family history of any cancer, p = 0.020) conferred a significantly increased risk of carrying a BRCA1 mutation compared with ovarian cancer patients without such a history. However, the majority of ovarian cancer patients with these family histories and other suggestive histories tested negative for mutations. Conclusions: Approximately 10% of ovarian cancers occur in association with genetic mutations known to predispose to the disease. A routinely obtained family history is an unreliable way to identify patients who might harbor mutations. The majority of ovarian cancer patients with suggestive family histories test negative for known gene mutations, perhaps suggesting the existence of additional undiscovered genes predisposing to ovarian cancer. (Am J Obstet Gynecol 1998;178:670-7.)

Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors

DNA replication errors (RERs) are closely associated with hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently, alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and hPMS2, have been implicated in the pathogenesis of HNPCC: Several studies have demonstrated RER in 13-17% of nonfamilial colorectal carcinomas. It is unclear, however, as to whether or not these RER positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC or are caused by incidental alterations of DNA mismatch repair genes. Consequently, the authors studied the characteristics of RER positive nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2 and hMLH1 gene mutations. Fresh or frozen samples of 103 nonfamilial colorectal carcinomas were examined for RERs using the polymerase chain reaction (PCR) and specific microsatellite primers. The authors also identified mutations of the hMSH2 and hMLH1 genes in RER positive samples by a PCR single strand conformational polymorphism analysis followed by direct nucleotide sequencing. The incidence of RER was 15.7% (17/103) in nonfamilial colorectal carcinomas, and only 1 case, which was found in the ascending colon, showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any of the remaining RER positive tumors. RER positive nonfamilial carcinomas tended to be located more frequently in the right colon. There was no increased prevalence in young patients, and the clinicopathologic characteristics of HNPCC were absent in the patients with RER positive nonfamilial colorectal carcinoma. Based on these findings, the carcinogenesis of RER positive nonfamilial colorectal carcinoma is considered different from that of HNPCC: