Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence

Nat Genet. 2021 Nov;53(11):1553-1563. doi: 10.1038/s41588-021-00928-6. Epub 2021 Oct 18.

Abstract

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC Deaminases / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Brazil / epidemiology
  • China / epidemiology
  • Esophageal Neoplasms / epidemiology*
  • Esophageal Neoplasms / genetics*
  • Esophageal Squamous Cell Carcinoma / epidemiology*
  • Esophageal Squamous Cell Carcinoma / genetics*
  • Female
  • Humans
  • Incidence
  • Iran / epidemiology
  • Male
  • Middle Aged
  • Mutation*
  • Tumor Suppressor Protein p53 / genetics
  • United Kingdom / epidemiology
  • Whole Genome Sequencing

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase, Mitochondrial
  • APOBEC Deaminases