Abstract Background: Hereditary non-polyposis colorectal cancer is the most common cause of early onset of hereditary colorectal cancer. In the majority of Hereditary non-polyposis colorectal cancer families, microsatellite instability and germline mutation in one of the DNA mismatch repair genes in clouding MSH2, MLH1, MSH6 and PMS2 are found. The Objective of this study was to determine the involvement of mismatch repair genes mutations in Iranian population, and microsatellite instability profile in patients with colorectal cancer. Methods: We analyzed 592 patients with colorectal cancer. The entire coding sequence of each gene was analyzed using direct sequencing. Results: We were able to find three novel MLH1 germline mutations in three Iranian patients suffering from Hereditary non-polyposis colorectal cancer. The first was a transversion mutation c.346A>C (T116P), which occured in the highly conserved HATPase-c region of MLH1 protein. The second was also a transversion mutation c.736A>T (I246L), which caused an amino acid change of Isoleucine to Leucine. The third mutation (c.2145,6 delTG) was frame shift mutation, and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in MLH1 gene. In all patients, an abnormal expression of MMR proteins was related to the above mutations. MSI assay revealed high instability in microsatellite for two patients and microsatellite stability for one patient. Conclusion: These novel mutations may imply the different characteristics of hereditary non-polyposis colorectal cancer in Iranian population as compared to reports from the western countries. KEYWORDS: HNPCC, mismatch repair, MMR, microsatellite instability, MLH1.

Keywords: KEYWORDS: HNPCC, mismatch repair, MMR, microsatellite instability, MLH1.

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