Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway
The first exome study of gallbladder cancer, in 57 Chinese patients, found TP53 mutated in about half and showed that the ErbB family of growth receptors (EGFR, HER2, HER3 and their partners) is the most commonly hit pathway, with a worse outlook when it is.
Overview
Somatic mutations were identified in 57 tumour-normal pairs of gallbladder carcinoma through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern was defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate below 0.05) of non-silent mutations were TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%).
ErbB signalling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) was the most extensively mutated pathway, affecting 36.8% (21 of 57) of the samples, and multivariate analysis showed that cases with ErbB pathway mutations had a worse outcome (P = 0.001).
- TP53 mutated in 47.1%, ERBB3 in 11.8% and KRAS in 7.8% of 57 gallbladder carcinomas.
- The ErbB pathway was mutated in 36.8% (21 of 57) and carried a worse outcome (P = 0.001).
- C>T mutations at TCN sites dominated the mutation spectrum.
This paper put HER-family signalling at the centre of gallbladder cancer biology a decade before HER2-directed drugs were approved for it, and it is why ERBB2 and ERBB3 sit near the top of every later panel study.
- 57 patients from one Chinese centre; frequencies in Chile, India and the West differ.
- Exome depth of the era; copy-number calls were limited.
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