Molecular Genetics of Gallbladder Cancer

Abstract

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.
close

References

Alexandrov LB, Nik‐Zainal S, Wedge DC, et al. (2013) Signatures of mutational processes in human cancer. Nature 500: 415–421.

Borger DR, Tanabe KK, Fan KC, et al. (2012) Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad‐based tumor genotyping. The Oncologist 17: 72–79.

Colotta F, Allavena P, Sica A, Garlanda C and Mantovani A (2009) Cancer‐related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30: 1073–1081.

Deshpande V, Nduaguba A, Zimmerman SM, et al. (2011) Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma. BMC Cancer 11: 60.

Garcia P, Manterola C, Araya JC, et al. (2009) Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Molecular Carcinogenesis 48: 79–89.

Goldin RD and Roa JC (2009) Gallbladder cancer: a morphological and molecular update. Histopathology 55: 218–229.

Guest RV, Boulter L, Kendall TJ, et al. (2014) Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Research 74: 1005–1010.

Hansel DE, Meeker AK, Hicks J, et al. (2006) Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma. Modern Pathology 19: 772–779.

Heaphy CM, Subhawong AP, Hong SM, et al. (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. The American Journal of Pathology 179: 1608–1615.

Hsing AW, Bai Y, Andreotti G, et al. (2007) Family history of gallstones and the risk of biliary tract cancer and gallstones: a population‐based study in Shanghai, China. International Journal of Cancer Journal International du Cancer 121: 832–838.

Jain K, Mohapatra T, Das P, et al. (2014) Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer. Annals of Surgery 260 (6): 1073–1080.

Javle M, Rashid A, Churi C, et al. (2014) Molecular characterization of gallbladder cancer using somatic mutation profiling. Human Pathology 45: 701–708.

Jiao Y, Pawlik TM, Anders RA, et al. (2013) Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nature Genetics 45: 1470–1473.

Kandoth C, McLellan MD, Vandin F, et al. (2013) Mutational landscape and significance across 12 major cancer types. Nature 502: 333–339.

Kawamoto T, Krishnamurthy S, Tarco E, et al. (2007) HER receptor family: novel candidate for targeted therapy for gallbladder and extrahepatic bile duct cancer. Gastrointestinal Cancer Research 1: 221–227.

Krishnamurti U and Silverman JF (2014) HER2 in breast cancer: a review and update. Advances in Anatomic Pathology 21: 100–107.

Kuraishy A, Karin M and Grivennikov SI (2011) Tumor promotion via injury‐ and death‐induced inflammation. Immunity 35: 467–477.

Leal P, Garcia P, Sandoval A, et al. (2013a) AKT/mTOR substrate P70S6K is frequently phosphorylated in gallbladder cancer tissue and cell lines. Onco Targets and Therapy 6: 1373–1384.

Leal P, Garcia P, Sandoval A, et al. (2013b) Immunohistochemical expression of phospho‐mTOR is associated with poor prognosis in patients with gallbladder adenocarcinoma. Archives of Pathology & Laboratory Medicine 137: 552–557.

Leitch A (1924) A British Medical Association Lecture on gall stones and cancer of the gall bladder: an experimental study. British Medical Journal 2: 451–454.

Letelier P, Brebi P, Tapia O and Roa JC (2012) DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer. Clinical Epigenetics 4: 11.

Li Q and Yang Z (2009) Expression of phospho‐ERK1/2 and PI3‐K in benign and malignant gallbladder lesions and its clinical and pathological correlations. Journal of Experimental & Clinical Cancer Research 28: 65.

Li M, Zhang Z, Li X, et al. (2014) Whole‐exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nature Genetics 46: 872–876.

Liu DC and Yang ZL (2011) Overexpression of EZH2 and loss of expression of PTEN is associated with invasion, metastasis, and poor progression of gallbladder adenocarcinoma. Pathology, Research and Practice 207: 472–478.

Lunardi A, Webster KA, Papa A, et al. (2014) Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget 5: 894–900.

Luzar B, Poljak M, Cor A, Klopcic U and Ferlan‐Marolt V (2005) Expression of human telomerase catalytic protein in gallbladder carcinogenesis. Journal of Clinical Pathology 58: 820–825.

Martinez E, Yoshihara K, Kim H, et al. (2014) Comparison of gene expression patterns across 12 tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects. Oncogene. DOI:10.1038/onc.2014.216. http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2014216a.html

Moreno M, Pimentel F, Gazdar AF, Wistuba II and Miquel JF (2005) TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma. Annals of Hepatology 4: 192–199.

Nakazawa K, Dobashi Y, Suzuki S, et al. (2005) Amplification and overexpression of c‐erbB‐2, epidermal growth factor receptor, and c‐met in biliary tract cancers. The Journal of Pathology 206: 356–365.

Niwa T and Ushijima T (2010) Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Advances in Genetics 71: 41–56.

Pai RK and Mojtahed K (2011) Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. Applied Immunohistochemistry & Molecular Morphology 19: 133–140.

Roa I, Araya JC, Villaseca M, et al. (1996) Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology 111: 232–236.

Roa I, Ibacache G, Melo A, et al. (2002) Subserous gallbladder carcinoma: expression of cadherine‐catenine complex. Revista Médica de Chile 130: 1349–1357.

Roa JC, Vo Q, Araya JC, et al. (2004) Inactivation of CDKN2A gene (p16) in gallbladder carcinoma. Revista Médica de Chile 132: 1369–1376.

Roa JC, Roa I, Correa P, et al. (2005) Microsatellite instability in preneoplastic and neoplastic lesions of the gallbladder. Journal of Gastroenterology 40: 79–86.

Roa I, de Aretxabala X, Araya JC and Roa J (2006a) Preneoplastic lesions in gallbladder cancer. Journal of Surgical Oncology 93: 615–623.

Roa JC, Anabalon L, Roa I, et al. (2006b) Promoter methylation profile in gallbladder cancer. Journal of Gastroenterology 41: 269–275.

Roa I, de Toro G, Schalper K, et al. (2014a) Overexpression of the HER2/neu gene: a new therapeutic possibility for patients with advanced gallbladder cancer. Gastrointestinal Cancer Research 7: 42–48.

Roa I, Ibacache G, Munoz S and de Aretxabala X (2014b) Gallbladder cancer in Chile: pathologic characteristics of survival and prognostic factors: analysis of 1,366 cases. American Journal of Clinical Pathology 141: 675–682.

Saetta AA, Papanastasiou P, Michalopoulos NV, et al. (2004) Mutational analysis of BRAF in gallbladder carcinomas in association with K‐ras and p53 mutations and microsatellite instability. Virchows Archiv: An International Journal of Pathology 445: 179–182.

Shi YZ, Hui AM, Li X, Takayama T and Makuuchi M (2000) Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clinical Cancer Research 6: 4096–4100.

Simbolo M, Fassan M, Ruzzenente A, et al. (2014) Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget 5: 2839–2852.

Sorscher S (2013) Marked radiographic response of a HER‐2‐overexpressing biliary cancer to trastuzumab. Cancer Management and Research 9: 1–3.

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

Tadokoro H, Shigihara T, Ikeda T, Takase M and Suyama M (2007) Two distinct pathways of p16 gene inactivation in gallbladder cancer. World Journal of Gastroenterology 13: 6396–6403.

Wistuba II, Sugio K, Hung J, et al. (1995) Allele‐specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile. Cancer Research 55: 2511–2515.

Wistuba II, Miquel JF, Gazdar AF and Albores‐Saavedra J (1999) Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas. Human Pathology 30: 21–25.

Wistuba II, Ashfaq R, Maitra A, et al. (2002a) Fragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma. The American Journal of Pathology 160: 2073–2079.

Wistuba II, Maitra A, Carrasco R, et al. (2002b) High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma. British Journal of Cancer 87: 432–440.

Yoshida T, Sugai T, Habano W, et al. (2000) Microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis. Journal of Gastroenterology 35: 768–774.

Further Reading

Goldin RD and Roa JC (2009) Gallbladder cancer: a morphological and molecular update. Histopathology 55: 218–229.

Grivennikov SI, Greten FR and Karin M (2010) Immunity, inflammation, and cancer. Cell 140: 883–899.

Hundal R and Shaffer EA (2014) Gallbladder cancer: epidemiology and outcome. Clinical Epidemiology 6: 99–109.

Lazcano‐Ponce EC, Miquel JF, Munoz N, et al. (2001) Epidemiology and molecular pathology of gallbladder cancer. CA: A Cancer Journal for Clinicians 51: 349–364.

Letelier P, Brebi P, Tapia O and Roa JC (2012) DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer. Clinical Epigenetics 4: 11.

McNamara MG, Metran‐Nascente C and Knox JJ (2013) State‐of‐the‐art in the management of locally advanced and metastatic gallbladder cancer. Current Opinion in Oncology 25: 425–431.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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. http://www.els.net [doi: 10.1002/9780470015902.a0024921]