Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway

Nat Genet. 2014 Aug;46(8):872-6. doi: 10.1038/ng.3030. Epub 2014 Jul 6.


Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma / enzymology
  • Carcinoma / genetics*
  • Cell Line
  • Cell Line, Tumor
  • ErbB Receptors / genetics*
  • Exome*
  • Female
  • Gallbladder Neoplasms / enzymology
  • Gallbladder Neoplasms / genetics*
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Recurrence, Local / enzymology
  • Neoplasm Recurrence, Local / genetics*
  • Signal Transduction / genetics


  • EGFR protein, human
  • ErbB Receptors