Germline susceptibility from broad genomic profiling of pediatric brain cancers

Abstract

Identifying germline predisposition in CNS malignancies is of increasing clinical importance, as it contributes to diagnosis and prognosis, and determines aspects of treatment. Inclusion of germline testing has historically been limited due to challenges surrounding access to genetic counseling, complexity in acquiring a germline comparator specimen, concerns about the impact of findings, or cost considerations. These limitations were further defined by the breadth and scope of clinical testing to precisely identify complex variants as well as concerns regarding the clinical interpretation of variants including those of uncertain significance. In the course of conducting an IRB approved protocol that performed genomic, transcriptomic and methylation-based characterization of pediatric CNS malignancies, we catalogued germline predisposition to cancer based on paired exome capture sequencing, coupled with computational analyses to identify variants in known cancer predisposition genes and to interpret them relative to established clinical guidelines. In certain cases, these findings refined diagnosis or prognosis, or provided important information for treatment planning. We outline our aggregate findings on cancer predisposition within this cohort which identified 16% of individuals (27 of 168) harboring a variant predicting cancer susceptibility and contextualize the impact of these results in terms of treatment-related aspects of precision oncology.