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 -