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

TY - JOUR

T1 - Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns

AU - Sørensen, Simon Grund

AU - Shrikhande, Amruta

AU - Poulsgaard, Gustav Alexander

AU - Christensen, Mikkel Hovden

AU - Bertl, Johanna

AU - Laursen, Britt Elmedal

AU - Hoffmann, Eva R

AU - Pedersen, Jakob Skou

N1 - © 2023, Sørensen et al.

PY - 2023/3/8

Y1 - 2023/3/8

N2 - 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.

AB - 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.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - DNA Helicases/genetics

KW - DNA Repair-Deficiency Disorders

KW - DNA Repair/genetics

KW - DNA damage response

KW - Humans

KW - Male

KW - Mutation

KW - Neoplasms/genetics

KW - Nuclear Proteins/genetics

KW - Transcription Factors/genetics

KW - mutational signatures

KW - personalised medicine

KW - predictive modelling

KW - repair deficiency

U2 - 10.7554/elife.81224

DO - 10.7554/elife.81224

M3 - Journal article

C2 - 36883553

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e81224

ER -