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

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Sørensen, Simon Grund
Amruta Shrikhande
Gustav A. Poulsgaard
Mikkel H. Christensen
Johanna Bertl
Laursen, Britt Elmedal
Hoffmann, Eva
Jakob S. Pedersen

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 DDR 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 ROC 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.

Originalsprog	Engelsk
Artikelnummer	e81224
Tidsskrift	eLife
Vol/bind	12
ISSN	2050-084X
DOI	https://doi.org/10.7554/elife.81224
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
ERH and AS were funded by the Novo Nordisk Foundation (NNF15OC0016662), Cancer

Funding Information:
ERH and AS were funded by the Novo Nordisk Foundation (NNF15OC0016662), Cancer Research UK (C23210/A7574), and the Danish National Research Foundation (Center grant, DNRF115). JSP, SGS, GAP, and MHC were funded by the Independent Research Fund Denmark | Medical Sciences (8021-00419B), the Danish Cancer Society (R307-A17932), Aarhus University Research Foundation (AUFF-E-2020-6-14), a PhD stipend from Aarhus University, and a stipend from Research Foundation of Central Region Denmark (A2972).

Funding Information:
administration, which was supported by statistical predictions of homologous recombination

Funding Information:
by MSH3-d may have caused the majority of their LOF events. This notion is supported by

Funding Information:
Research UK (C23210/A7574), and the Danish National Research Foundation (Center grant,

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© 2023, eLife Sciences Publications Ltd. All rights reserved.

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