Molecular Genetics of Gallbladder Cancer


Gallbladder cancer (GBC) is a deadly biliary neoplasia with marked ethnic and geographical distribution. The prognosis of GBC is often dismal due to late diagnosis and lack of effective therapeutic options. The main risk factor for GBC is gallstone carriage over long periods of time, which leads to persistent damage and chronic inflammation. This condition promotes genetic/epigenetic alterations and the progressive impairment of the epithelial architecture, mainly through a metaplasia–dysplasia–carcinoma sequence. New molecular alterations have been identified that may help improve the clinical management of patients through the application of more specific therapies. The application of new DNA sequencing technologies is making it possible to catalogue the spectrum of genetic alterations that characterise GBC and is aiding in the understanding of the biology behind gallbladder carcinogenesis. Here, a stepwise model of morphogenetic progression from inflammatory to neoplastic tissues is proposed based on currently available evidence.

Key Concepts

  • Gallbladder cancer is essentially an inflammatory disease, primarily caused by chronic exposure of the epithelium to gallstones.
  • Morphological alterations of the epithelium arise mainly through a metaplasia–dysplasia–carcinoma sequence.
  • Inactivation of tumour suppressor pathway is an early and important carcinogenic event for gallbladder cancer.
  • Genome‐level alterations such as loss of heterozygosity, microsatellite instability and epigenetic alterations arise early during gallbladder carcinogenesis and increase progressively to advanced stages.
  • Prevention of chronic inflammation may reduce the onset of early genetic alterations and therefore contribute to reducing gallbladder cancer mortality.
  • A future challenge is to elucidate molecular subtypes of GBC and identify new potential therapeutic targets in order to improve patient survival.

Keywords: gallbladder cancer; chronic cholecystitis; gallstones; chronic inflammation; TP53; CDKN2A; KRAS; ErbB pathway

Figure 1. Morphogenetic progression of gallbladder cancer. Loss of heterozygosity and epigenetic alterations are two of the earliest genome‐level modifications observed in epithelial tissues exposed to chronic inflammation. Inactivation of TP53, CDKN2A and FHIT, for mutations (Mut), hypermethylation (HyMe) or deletions (LOH), are important triggers for gallbladder carcinogenesis. KRAS/BRAF mutations are mainly observed in invasive tumours.


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Further Reading

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Stinton LM and Shaffer EA (2012) Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and Liver 6: 172–187.

Wistuba II and Gazdar AF (2004) Gallbladder cancer: lessons from a rare tumour. Nature Reviews Cancer 4: 695–706.

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Espinoza, Jaime A, García, Patricia, Bizama, Carolina, and Roa, Juan C(Mar 2015) Molecular Genetics of Gallbladder Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024921]