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Mutation of a mutL homolog in hereditary colon cancer
N Papadopoulos1, N C Nicolaides, Y F Wei
1Johns Hopkins Oncology Center, Baltimore, MD 21231.
Abstract:
Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS-related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes (hMLH1) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.
Insights
Alterations in mismatch repair genes, like hMLH1, cause hereditary nonpolyposis colorectal cancer (HNPCC). This study identified new human mismatch repair genes, including hMLH1, linking them to HNPCC susceptibility.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Hereditary nonpolyposis colorectal cancer (HNPCC) is linked to DNA mismatch repair gene defects.
- Previous research identified mutS-related genes involved in some HNPCC cases.
Purpose of the Study:
- To identify additional human mismatch repair genes.
- To investigate the role of these genes in hereditary nonpolyposis colorectal cancer.
Main Methods:
- Searched a large expressed sequence tag database for human mismatch repair genes.
- Utilized genetic linkage analysis to map identified genes.
- Screened for mutations in candidate genes within HNPCC families.
Main Results:
- Discovered three new human mismatch repair genes related to bacterial mutL.
- Localized one gene, hMLH1, to chromosome 3p21, near known HNPCC susceptibility markers.
- Identified disease-causing mutations in hMLH1 in HNPCC kindreds.
Conclusions:
- The hMLH1 gene is a significant cause of hereditary nonpolyposis colorectal cancer.
- Defects in multiple mismatch repair genes can lead to HNPCC.
- This expands the understanding of genetic pathways in colorectal cancer development.