Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer

Microsatellite instability (MSI) is characteristic of hereditary nonpolypos is colorectal cancer, and occurs in a subset (10 to 15%) of unselected colo rectal cancer cases. In hereditary nonpolyposis colorectal cancer, MSI is c aused by defects in five mismatch repair genes, and in sporadic cases the m ain cause seems to be somatic MLH1 promoter methylation. Most Likely additi onal hereditary nonpolyposis colorectal cancer genes remain to be discovere d. Genes with simple repeats in their coding region are often targets for d eletions in MSI-positive tumors. Several genes (TGF beta RII, IGFIIR, MSH3, MSH6, BAX, MBD4) with significance in tumorigenesis harbor repeats in thei r coding regions and are often somatically inactivated because of deletions causing frameshifts, Recently, a novel human mismatch repair gene, MLH3, w as cloned and shown to be involved in mammalian mismatch repair. To evaluat e the possible role of MLH3 in hereditary cancer, we performed germline sin gle-strand conformation polymorphism-analysis for 52 patients displaying fe atures of inherited colorectal cancer. Forty-six of these had been diagnose d with MSI-positive tumors. No germline mutations were found. Similar to MS H3 and MSH6, MLH3 harbors mononucleotide repeats, ie, (A(6))-(A(9)), in its coding region, which makes it a putative target for somatic mutations in M SI-positive tumors, To evaluate its somatic inactivation we performed a del etion search focusing on eight exonic MLH3 mononucleotide repeats in a seri es of 93 MSI-positive tumors, Somatic deletions were found In 8.6% of the s amples, a frequency similar to one detected in neutral noncoding mononucleo tide repeats. No evidence of involvement of MLH3 in MSI tumorigenesis was o btained.