Genetic Analysis of Functional Rare Germline Variants across Nine Cancer Types from an Electronic Health Record Linked Biobank.

Abstract

Rare variants play an essential role in the etiology of cancer. In this study, we aim to characterize rare germline variants that impact the risk of cancer. We performed a genome-wide rare variant analysis using germline whole exome sequencing (WES) data derived from the Geisinger MyCode initiative to discover cancer predisposition variants. The case-control association analysis was conducted by binning variants in 5,538 patients with cancer and 7,286 matched controls in a discovery set and 1,991 patients with cancer and 2,504 matched controls in a validation set across nine cancer types. Further, The Cancer Genome Atlas (TCGA) germline data were used to replicate the findings. We identified 133 significant pathway-cancer pairs (85 replicated) and 90 significant gene-cancer pairs (12 replicated). In addition, we identified 18 genes and 3 pathways that were associated with survival outcome across cancers (Bonferroni P < 0.05). In this study, we identified potential predisposition genes and pathways based on rare variants in nine cancers. This work adds to the knowledge base and progress being made in precision medicine.