Genetic Predisposition to Atypical Teratoid/Rhabdoid Tumor Caused by Mutations in SWI/SNF Complex Genes

Background

Atypical teratoid rhabdoid tumors (AT/RTs) are highly malignant neoplasms of the central nervous system (CNS), typically found in very young children. Although AT/RTs represent only 3% of pediatric CNS tumors, they account for 10% of all deaths among children with CNS tumors. A substantial proportion of AT/RT patients harbor germline loss-of-function mutations in the gene SMARCB1, a component of the SWI/SNF chromatin remodeling complex involved in neural development. It is currently unknown what proportion of children diagnosed with AT/RT, at the population level, harbor germline SMARCB1 mutations.

Project Goal

We propose to address these questions in a population-based sample of children diagnosed with AT/RT, nested within the California Birth Cohort (CBC). We have retrieved archived neonatal bloodspots from all Californian children diagnosed with an AT/RT between 1998 and 2010. DNA samples from these children will be analyzed using PCR and Sanger sequencing to identify coding mutations in the nine exons of SMARCB1. Additionally, DNA specimens that do not harbor SMARCB1 point mutations will undergo genome-wide genotyping. By leveraging the unique and mature resources within the California Birth Cohort, this registry-based approach will enable analysis of a large and truly population-based sample of AT/RT patients, helping to determine just what proportion of these devastating tumors are attributable to mutations of this single gene. By analyzing DNA specimens collected at birth, we can successfully perform epidemiologic research on this orphan pediatric cancer.