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The MLH1 gene, located on Chromosome 3p21, is one of 5 mismatch repair genes (hMLH-1, hMSH-2, hMSH-6, PMS-2, hMLH-3) involved in the repair of mismatch nucleotides following DNA replication or repair. The defective MLH1 gene contributes to the development of sporadic colorectal carcinoma, while germline MLH1 mutations are responsible for approximately 35% of inherited, non-polyposis colorectal carcinoma (HNPCC). Individuals with an HNPCC gene mutation have approximately a 70%-80% lifetime risk of developing colon or rectal cancer. Most tumors from HNPCC patients have defective mismatch repair gene due to insertion or deletion of repeated units in the genome. This phenomenon, known as microsatellite instability (MSI) is found in the colorectal cancer DNA, but not in the adjacent normal colorectal mucosa. Primary antibodies by immunohistochemistry (IHC) that recognize mismatch repair protein expresssion can be used as a primary screening test or as a secondary tool to find germline mutations in a specific gene and may have prognostic and treatment implications for the cancer patient as well as at risk relatives. Lack of expression of either hMSH2 or hMLH1 by IHC in tumors is correlated with MSI in the tumor. The majority of MSI observed in sporadic cases seem to be caused by somatic hypermethylation of the hMLH1 promoter. It has also been observed that absent hMSH2 IHC expression is associated with germline hMSH2 mutation, and a minority of absent hMLH1 IHC expression is associated with germline hMLH1 mutation. IHC for these 2 genes is now transitioning into routine clinical practice. hMLH-1 is currently a part of the HNPCC profile which also includes hMSH-2, PMS-2, and MSH-6, but can also be ordered individually. For more information contact Dr. Raheela Ashfaq at Veripath OncoDiagnostics at 214-645-7053 or Raheela.Ashfaq@UTSouthwestern.edu
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