Affiliation:
1. Department of Molecular Medicine (MOMA), Aarhus University Hospital
2. Department of Clinical Medicine, Aarhus University
3. DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen
4. Department of Biomedicine, Aarhus University
5. Bioinformatics Research Center (BiRC), Aarhus University
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.
Funder
Novo Nordisk Fonden
Cancer Research UK
Danmarks Frie Forskningsfond
Kræftens Bekæmpelse
Aarhus Universitets Forskningsfond
Sundhedsvidenskabelige Fakultet, Aarhus Universitet
Sundhed, Region Midtjylland
Danmarks Grundforskningsfond
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience