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

• DOI: 10.1371/journal.pgen.1008572
• Publication Date: 2020-02-03T13:33:56Z
• Authors: Hu Fang; Jayne A. Barbour; Rebecca C. Poulos; Riku Katainen; Lauri A. Aaltonen; Jason W. H. Wong
• Keywords: 0301 basic medicine; Carcinogenesis; POLYMERASE-EPSILON; DNA Mutational Analysis; DNA-POLYMERASE; Datasets as Topic; QH426-470; BINDING-SITES; Epigenesis, Genetic; MISMATCH REPAIR; Cytosine; 03 medical and health sciences; Protein Domains; GERMLINE; Databases, Genetic; Genetics; Humans; Poly-ADP-Ribose Binding Proteins; SIGNATURES; 0303 health sciences; LANDSCAPE; Whole Genome Sequencing; DNA Polymerase II; DNA Methylation; 3. Good health; Biomedicine; NUCLEOTIDE EXCISION-REPAIR; Genetics, developmental biology, physiology; REPLICATION; Mutation; PATTERNS; CpG Islands; Tumor Suppressor Protein p53; Colorectal Neoplasms; Research Article

AbstractCancer 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 and yet, how these POLE mutants generate mutations across cancer genomes and influence driver events remains poorly understood. Here we analyzed 7,345 colorectal cancer samples, including nine whole genome sequenced samples harboring POLE mutations. Our analysis identified differential mutation spectra across the mutants including methylation-independent enrichment of C>T mutations in POLE V411L. In contrast, analysis of other genomic regions showed similar mutation profiles across the different POLE mutants. Notably, we found that POLE mutants with the TP53 R213* mutation, caused by a TT[C>T]GA substitution, have significantly higher relative frequency of this mutational context compared with samples without this mutation. This finding demonstrates that variations in underlying mutation spectra can increase the likelihood of specific driver mutation formation.