Abstract 1846: Identification of a germline mutation in PMS2, a DNA mismatch repair gene, in a large consanguineous family with a history of Pediatric GBMs

Glioblastoma multiforme (GBM) is the most frequent and malignant human brain tumor. It is widely accepted that human cancer is a genetic disease caused by sequential accumulation of cancer gene mutations. Specifically, the gene or genes which initiate GBM formation has yet to be identified. Through collaboration with the Pakistani National Genetic Institute we have identified a consanguineous family presenting with a history of Pediatric GBMs to conduct comprehensive genomic analysis in hopes of identifying this “gatekeeper” gene. In this pedigree four children are deceased from GBM while an additional five infants have died within 4 days of birth without diagnosis. GBM has been the only diagnosed cancer in this family, indicating the existence of a GBM-specific germline mutation as a causative agent for the GBM clinical phenotype. Comprehensive genomic analysis has been conducted to elucidate a genetic aberration which is inherited and can be attributed to the GBM presenting clinical phenotype. We have collected blood and tumor DNAs for this family and performed sequencing on numerous genes including TP53, APC, IDH1, IDH2, PMS2, MLH1, MSH2, and, MSH6. Sequencing has successfully identified a germline frame shift mutation (p.Y181X) in PMS2. All affected patients have a homozygous mutation while their parents are both heterozygous carriers, suggesting the homozygous inheritance of this mutation is a causative agent for the GBM clinical phenotype. Our study suggests that the PMS2 inherited homozygous mutation could be a critical event in GBM formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1846.