A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

Alessandra Viel, Alessandro Bruselles, Ettore Meccia, Mara Fornasarig, Michele Quaia, Vincenzo Canzonieri, Eleonora Policicchio, Emanuele Damiano Urso, Marco Agostini, Maurizio Genuardi, Emanuela Lucci-Cordisco, Tiziana Venesio, Aline Martayan, Maria Grazia Diodoro, Lupe Sanchez-Mete, Vittoria Stigliano, Filomena Mazzei, Alessandro Giuliani, Francesca Grasso, Marta BaiocchiRoberta Maestro, Giuseppe Giannini, Marco Tartaglia, Ludmil B Alexandrov, Margherita Bignami

Research output: Contribution to journalArticle

Abstract

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.

Original languageEnglish
Pages (from-to)39-49
Number of pages11
JournalEBioMedicine
Volume20
DOIs
Publication statusPublished - Jun 2017

Keywords

  • Alleles
  • Colorectal Neoplasms/genetics
  • DNA Damage
  • DNA Glycosylases/genetics
  • DNA Mutational Analysis
  • DNA Repair
  • Gene Frequency
  • Genes, Tumor Suppressor
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Guanine/analogs & derivatives
  • Humans
  • Microsatellite Instability
  • Mutation
  • Mutation Rate
  • Oncogenes
  • Whole Exome Sequencing

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  • Cite this

    Viel, A., Bruselles, A., Meccia, E., Fornasarig, M., Quaia, M., Canzonieri, V., Policicchio, E., Urso, E. D., Agostini, M., Genuardi, M., Lucci-Cordisco, E., Venesio, T., Martayan, A., Diodoro, M. G., Sanchez-Mete, L., Stigliano, V., Mazzei, F., Giuliani, A., Grasso, F., ... Bignami, M. (2017). A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. EBioMedicine, 20, 39-49. https://doi.org/10.1016/j.ebiom.2017.04.022