Mutations in ERBB family receptors or downstream effectors are found in 37% of gallbladder carcinomas.

  • Major finding: Mutations in ERBB family receptors or downstream effectors are found in 37% of gallbladder carcinomas.

  • Clinical relevance: ERBB pathway mutations are associated with poor clinical outcome.

  • Impact: Therapies targeting the ERBB receptor family may be effective in a subset of gallbladder carcinomas.

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Gallbladder carcinoma is an aggressive, highly metastatic cancer of the biliary tract, with a median survival time of less than 1 year. To characterize the mutational spectrum of gallbladder carcinoma and identify potential therapeutic targets, Li, Zhang, Li, and colleagues performed whole-exome or targeted gene sequencing on a total of 57 gallbladder carcinomas and matched normal tissues. Notably, few recurrently mutated genes identified overlapped with significantly mutated genes identified in cholangiosarcoma, suggesting that these tumors of the biliary epithelium are genetically distinct entities. In addition to frequent mutations in TP53, which was mutated in 47% of tumors, there were also recurrent somatic mutations affecting the ERBB family of receptor tyrosine kinases, with mutations in ERBB3 (HER3) in 12% of tumors, ERBB2 (HER2) in 10% of tumors, ERBB1 (EGFR) in 4% of tumors, and ERBB4 (HER4) in 4% of tumors. Altogether, the ERBB pathway was the most significantly mutated pathway, and mutations in ERBB receptors or downstream effectors were identified in 37% of gallbladder carcinomas. Expression of the identified HER2 and HER3 mutants significantly increased the proliferation of gallbladder carcinoma cell lines and nonmalignant cells, and combined knockdown of EGFR, HER2, and HER3 suppressed the growth and motility of gallbladder carcinoma cells, suggesting that ERBB receptor mutations are driving events in gallbladder carcinoma. Moreover, patients who had ERBB pathway mutations had a significantly shorter survival time than those who did not, further indicating that activation of the ERBB pathway may contribute to the progression of gallbladder carcinoma. Collectively, these results provide a rationale for evaluating the activity of ERBB pathway-targeted therapies that are clinically available or in development in patients with gallbladder carcinoma.

Li M, Zhang Z, Li X, Ye J, Wu X, Tan Z, et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet 2014 Jul 6 [Epub ahead of print].

©2014 American Association for Cancer Research.
2014