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

Simon Grund Sørensen, Amruta Shrikhande, Gustav Alexander Poulsgaard, Mikkel Hovden Christensen, Johanna Bertl, Britt Elmedal Laursen, Eva R Hoffmann*, Jakob Skou Pedersen

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

4 Citationer (Scopus)

Abstract

DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 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 BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 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 ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, 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.

OriginalsprogEngelsk
Artikelnummere81224
TidsskrifteLife
Vol/bind12
Antal sider27
ISSN2050-084X
DOI
StatusUdgivet - 8 mar. 2023

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