Soerensen, S. G. | Search bioRxiv

bioRxiv2022

The replication stress response suppresses mutation rates in mismatch repair deficient budding yeast and human cancers

Elevated mutation rate is a hallmark of mismatch repair (MMR) deficient cells and tumours. This includes microsatellite instability (MSI), which is caused by insertions and deletions in mono-and dinucleotide repeats. MSI rates, however, are highly variable across MMR-deficient tumours. Here we show that mutation rates are genetically regulated in MMR-deficient cells. A genome-wide deletion screen in budding yeast revealed that 3% gene deletions caused mutation rates to be further elevated, whereas 11% reduced mutation rates. The genes causing an elevation are enriched for DNA repair and replication processes, whereas deletion of genes implicated in transcriptional processes reduce mutation rates. A pan-cancer analysis of MSI revealed that mutations in replication stress response (ATR, TOPBP1, CHEK1) or DNA repair genes (RAD50, TOP3A) was associated with extreme rates of MSI in MMR-defective tumours, but not when mutated on their own. Since replication stress, DNA damage and repair activities are cell-type specific, this may account for highly variable mutation rates associated with different MMR-deficient tumours.

cancer biology↗

bioRxiv2022

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

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.

genomics↗