Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers

Nat Genet. 2013 Dec;45(12):1474-8. doi: 10.1038/ng.2806. Epub 2013 Nov 3.

Abstract

The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non-O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / parasitology*
  • Bile Ducts, Intrahepatic*
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / parasitology*
  • Exome / genetics*
  • Fasciola hepatica*
  • Fascioliasis / complications*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Male
  • Mutation
  • Sequence Analysis, DNA
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics

Substances

  • BAP1 protein, human
  • Tumor Suppressor Proteins
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • Ubiquitin Thiolesterase

Associated data

  • GEO/GSE49656
  • GEO/GSE49666