npj Precision Oncology (Jan 2023)

Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics

  • Myvizhi Esai Selvan,
  • Kenan Onel,
  • Sacha Gnjatic,
  • Robert J. Klein,
  • Zeynep H. Gümüş

DOI
https://doi.org/10.1038/s41698-023-00354-3
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 12

Abstract

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Abstract Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28–1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30–1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24–1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis.