Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns.

Abstract

DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of <i>BRCA1/2</i> and efficacy prediction for PARP inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DNA damage response genes based on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for <i>BRCA1/2</i>, <i>MSH3/6</i>, <i>TP53</i>, and <i>CDK12</i> LOF variants. <i>CDK12</i> is associated with tandem duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the receiver operator characteristic curve = 0.97). Our novel associations include mono- or biallelic LOF variants of <i>ATRX</i>, <i>IDH1</i>, <i>HERC2</i>, <i>CDKN2A</i>, <i>PTEN</i>, and <i>SMARCA4</i>, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.