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

Cancer Epidemiol Biomarkers Prev. 2021 Sep;30(9):1681-1688. doi: 10.1158/1055-9965.EPI-21-0082. Epub 2021 Jul 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Biological Specimen Banks
  • Biomarkers, Tumor / blood
  • Case-Control Studies
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Germ-Line Mutation
  • Humans
  • Male
  • Neoplasms / blood
  • Neoplasms / epidemiology
  • Neoplasms / genetics*


  • Biomarkers, Tumor