MLH1, MSH2 & MSH6 GENES

The isolation of four genes responsible for HNPCC (MLH1, MSH2, MSH6, and PMS2) has facilitated the molecular diagnosis of HNPCC. Individuals with HNPCC have inherited a nonfunctioning copy of one of these genes in their germline. When the remaining working copy is inactivated by a deleterious mutation, the cell loses its ability to repair mismatches of the DNA base pairs during DNA replication.

	MLH1, MSH2 and MSH6 are mismatch repair genes that correct mistakes that normally occur during DNA replication.

This is why these tumor suppressor genes are known as mismatch repair (MMR) genes. They are the DNA "proofreading" proteins that detect and repair DNA mismatches. The function of the gene product is to repair DNA mismatches; that is to repair mutations that if left unchecked may make a cell malignant. Mutations in these genes occur in sporadic cancers of the colon and endometrium but are infrequent.

The majority of HNPCC is due to mutations in MLH1, MSH2 or MSH6. The MLH1 and MSH2 genes were discovered in 1994, the former on chromosome 3p and the latter on chromosome 2p. The coding portion of the MLH1 gene is fairly large, made up of 2,271 base pairs on 19 exons. The coding portion of the MSH2 gene is slightly larger having 2,805 base pairs on 16 exons. The MSH6 gene was discovered in 1997 on chromosome 2p. The coding portion of the MSH6 is significantly larger than MLH1 and MSH2 , made up of 4,249 base pairs on 10 exons. Mutations are evenly distributed along the length of all three genes. Large deletions have been characterized (most often in MLH1 and MSH2), but no clustering of common mutations has been reported as seen in the BRCA genes and the Ashkenazi population. Because many families have their own private mutations, identification of germline mutations often requires fully sequencing the DNA throughout the genes.

	Mutations in MLH1, MSH2 and MSH6 account for the majority of genetically defined cases of hereditary nonpolyposis colorectal cancer.

MICROSATELLITE INSTABILITY
Microsatellites are repeating DNA sequences of unknown function found throughout the genome. Testing for microsatellite instability (MSI) is most often performed on colorectal cancer tumor tissue. MSI is demonstrated when the length of the repeated DNA sequences differs in the tumor tissue as compared with non-tumor tissue. This is an "acquired" genetic phenomenon found in the tumor but not in the germline. Over 95% of HNPCC-associated colorectal cancers express MSI. However, MSI is not only present in HNPCC associated colorectal tumors but is also found in 10-15% of sporadic colorectal tumors.

Because some sporadic tumors exhibit MSI, its presence requires further genetic analysis to determine whether an inherited germline mutation exists. Also, the absence of MSI cannot be used as a sole criterion to exclude the diagnosis of HNPCC because some HNPCC-related cancers have been shown to lack MSI, especially in patients with MSH6 mutations.

» More