Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE1 1: Considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers

Background: The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. Results: We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. Conclusion: Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.