Genetic Analysis of Functional Rare Germline Variants across Nine Cancer Types from an Electronic Health Record Linked Biobank
- 7 July 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 30 (9), 1681-1688
- https://doi.org/10.1158/1055-9965.EPI-21-0082
Abstract
Background: 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. Methods: 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. Results: 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). Conclusions: In this study, we identified potential predisposition genes and pathways based on rare variants in nine cancers. Impact: This work adds to the knowledge base and progress being made in precision medicine.Keywords
Funding Information
- NLM (R01 NL012535)
- Pennsylvania Department of Health (#SAP 4100070267)
- Geisinger Medical Center (SRC-075)
- NHGRI (T32HG009495-01)
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