Cancer-Driving Mutations Are Enriched in Genic Regions Intolerant to Germline Variation

Authors

Dimitrios Vitsios
Ryan S Dhindsa
Dorota Matelska
Jonathan Mitchell
Xuequing Zou
Joshua Armenia
Fengyuan Hu
Quanli Wang
Ben Sidders
Andrew R Harper
Slavé Petrovski

Publication Date

8-26-2022

Journal

Science Advances

DOI

10.1126/sciadv.abo6371

PMID

36026442

PMCID

PMC9417173

PubMedCentral® Posted Date

8-26-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Germ Cells, Germ-Line Mutation, Hematologic Neoplasms, Humans

Abstract

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. We hypothesized that cancer-driving mutations might be enriched in genic subregions that are depleted of germline variation relative to somatic variation. We introduce a new metric, OncMTR (oncology missense tolerance ratio), which uses 125,748 exomes in the Genome Aggregation Database (gnomAD) to identify these genic subregions. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Last, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR markedly improves genetic signals for hematologic malignancies.