Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer


Autoři: Hu Fang aff001;  Jayne A. Barbour aff001;  Rebecca C. Poulos aff003;  Riku Katainen aff004;  Lauri A. Aaltonen aff004;  Jason W. H. Wong aff001
Působiště autorů: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region aff001;  Prince of Wales Clinical School, UNSW Medicine, UNSW Sydney, New South Wales, Australia aff002;  Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia aff003;  Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland aff004;  Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland aff005
Vyšlo v časopise: Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008572
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008572

Souhrn

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.

Klíčová slova:

Cancer genomics – Colorectal cancer – DNA methylation – Methylation – Mutation – Nonsense mutation – Somatic mutation – Substitution mutation


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