Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns.
Simon Grund SørensenAmruta ShrikhandeGustav Alexander PoulsgaardMikkel Hovden ChristensenJohanna BertlBritt Elmedal LaursenEva R HoffmannJakob Skou PedersenPublished in: eLife (2023)
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.
Keyphrases
- dna repair
- genome wide
- copy number
- dna damage
- dna methylation
- dna damage response
- prostate cancer
- replacement therapy
- cell cycle
- cell proliferation
- genome wide identification
- squamous cell carcinoma
- gene expression
- oxidative stress
- stem cells
- papillary thyroid
- autism spectrum disorder
- bioinformatics analysis
- transcription factor
- childhood cancer
- squamous cell
- cell therapy
- smoking cessation
- high intensity
- lymph node metastasis