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Molecular Diagnosis and Targeting of Biliary Tract Cancer

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Molecular Diagnosis and Targeting for Thoracic and Gastrointestinal Malignancy

Part of the book series: Current Human Cell Research and Applications ((CHCRA))

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Abstract

Biliary tract cancer (BTC) is a highly aggressive malignant tumor arising from epithelial cells lining the bile duct and occurring at distinct anatomical locations: intrahepatic, extrahepatic, and the gallbladder. The incidence of BTC has increased globally; however, surgery is the only curative treatment, and no other effective therapies are available. Patients with BTC have a poor prognosis because most tumors are only detected at an advanced stage, making early diagnosis and treatment essential.

Recent developments in diagnosis and therapy for BTC, especially in the field of molecular biology, have resulted in better long-term survival rates, especially in patients undergoing curative resection at an early stage. This trend needs to continue to further improve prognosis in BTC patients. In addition, more effective molecular diagnosis and targeting therapies are needed to target essential biochemical and signaling pathways or mutant proteins that are required for tumor cell growth and survival. To this end, the field requires better molecular classification of BTC and more precise categorization of tumors with respect to prognosis such that clinicians can make more informed choices about surgical or nonsurgical therapies for individual patients.

This review focuses on the molecular diagnosis and targeting therapy for BTC in surgical and nonsurgical patients, as well as the special relationship between tumor behavior and anatomical specificity in this disease.

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References

  1. Voss JS, et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol. 2013;44:1216–22.

    Article  CAS  PubMed  Google Scholar 

  2. Arai Y, et al. Fibroblast growth receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59:1427–14134.

    Article  CAS  PubMed  Google Scholar 

  3. Nagino M. Perihilar cholangiocarcinoma: a surgeon’s system viewpoint on current topics. J Gastroenterol. 2012;47:1165–76.

    Article  PubMed  Google Scholar 

  4. Ebata T, et al. Proposal to modify the International Union against Cancer staging system for perihilar cholangiocarcinoma. Br J Surg. 2014;101:79–88.

    Article  CAS  PubMed  Google Scholar 

  5. Endo I, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.

    Article  PubMed  Google Scholar 

  6. Nakeeb A, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73. (discussion)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liver Cancer Study Group in Japan. The general rules for the clinical and pathological study of primary liver cancer. 6th ed. Tokyo: Kanehara & Co., Ltd.; 2015. (in Japanese)

    Google Scholar 

  8. Japanese Society of Hepato-Biliary-Pancreatic Surgery. General rules for clinical and pathological studies on cancer of the biliary tract. 6th ed. Tokyo: Kanehara & Co., Ltd.; 2013. (in Japanese)

    Google Scholar 

  9. Miyazaki M, et al. Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: 3rd English edition. J Hepato Biliary Pancreatic Sci. 2015;22:181–96.

    Article  Google Scholar 

  10. Lu J, et al. Microrna expression profiles classify human cancers. Nature. 2005;435:834–8.

    Article  CAS  PubMed  Google Scholar 

  11. Reinhart BJ, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis Elegans. Nature. 2000;403:901–6.

    Article  CAS  PubMed  Google Scholar 

  12. Latelier P, et al. Circulating microRNAs as biomarkers in biliary tract cancers. Int J Mol Sci. 2016;17:791–814.

    Article  Google Scholar 

  13. Ruzzenente A, et al. Role of surgery in the treatment of intrahepatic cholangiocarcinoma. Eur Rev Med Pharmacol Sci. 2015;19:2892–900.

    CAS  PubMed  Google Scholar 

  14. Jones RP, et al. Prognostic molecular markers in resected extrahepatic biliary tract cancers; a systemic review and meta-analysis of immunohistochemically detected biomarkers. Biomark Med. 2015;9:763–75.

    Article  CAS  PubMed  Google Scholar 

  15. Fujimoto A, et al. Whole-genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat Commun. 2015;6:6120–7.

    Article  CAS  PubMed  Google Scholar 

  16. Lee CH, et al. Viral hepatitis-associated with intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma. Br J Cancer. 2009;100:1765–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Churi CR, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383–405.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Simbolo M, et al. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget. 2014;5:2839–52.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ruzzenente A, et al. Cholangiocarcinoma heterogeneity revealed by multigene mutational profiling: clinical and prognostic relevance in surgically resected patients. Ann Surg Oncol. 2016;23:1699–707.

    Article  PubMed  Google Scholar 

  20. Jiao Y, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinoma. Nat Genet. 2013;45:1470–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meng X, et al. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade. Cancer Treat Rev. 2015;41:868–76.

    Article  CAS  PubMed  Google Scholar 

  22. Gani F, et al. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2016;23:2610–7.

    Article  PubMed  Google Scholar 

  23. Liebe R, et al. Modifiable factors and genetic predisposition associated with gallbladder cancer. A concise review. J Gastrointestin Liver Dis. 2015;24:339–48.

    PubMed  Google Scholar 

  24. Zatonski WA, et al. Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH program of the International Agency for Research on Cancer. J Natl Cancer Inst. 1997;89:1132–8.

    Article  CAS  PubMed  Google Scholar 

  25. Liu X, et al. MiR-138 suppressed nasopharyngeal carcinoma growth and tumorigenesis by targeting the CCND1 oncogene. Cell Cycle. 2012;11:2495–506.

    Article  CAS  PubMed  Google Scholar 

  26. Zhao X, et al. miR-138 might reverse multidrug resistance of leukemia cells. Leuk Res. 2010;34:1078–82.

    Article  CAS  PubMed  Google Scholar 

  27. Gao Y, et al. miR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124. Biochem Biophys Res Commun. 2014;446:179–86.

    Article  CAS  PubMed  Google Scholar 

  28. Ma F, et al. MiR-138 suppresses cell proliferation by targeting bag-1 in gallbladder carcinoma. PLoS One. 2015;10:e126499–510.

    Google Scholar 

  29. Lazcano-Ponce EC, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin. 2001;51:349–64.

    Article  CAS  PubMed  Google Scholar 

  30. Fujii K, et al. High frequency of p53 gene mutation in adenocarcinomas of the gallbladder. Cancer Epidemiol Biomark Prev. 1996;5:461–6.

    CAS  Google Scholar 

  31. Shukla VK, et al. Telomerase activation-one step on the road to carcinoma of the gall bladder. Anticancer Res. 2006;26:4761–6.

    CAS  PubMed  Google Scholar 

  32. Kumari N, et al. Mutation profiling in gallbladder cancer in Indian population. Indian J Pathol Microbiol. 2014;57:9–12.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Deshpande V, et al. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma. BMC Cancer. 2011;11:60–6.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kazmi HR, et al. Prognostic significance of K-ras codon 12 mutation in patients with resected gallbladder cancer. Dig Surg. 2013;30:233–9.

    Article  CAS  PubMed  Google Scholar 

  35. Kim K, et al. Expression of cell cycle-related proteins, p16, p53 and p63 as important prognostic markers in gallbladder adenocarcinoma. Pathol Oncol Res. 2014;20:409–15.

    Article  CAS  PubMed  Google Scholar 

  36. Ghosh M, et al. p53 and beta-catenin expression in gallbladder tissues and correlation with tumor progression in gallbladder cancer. Saudi J Gastroenterol. 2013;19:34–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dixit R, et al. Molecular alterations in gallbladder cancer. World J Pathol. 2012;1:31–4.

    Google Scholar 

  38. Kuroki T, et al. Genetic alterations in gallbladder carcinoma. Surg Today. 2005;35:101–5.

    Article  CAS  PubMed  Google Scholar 

  39. Xuan YH, et al. An immunohistochemical study of the expression of cell-cycle-regulated proteins p53, cyclin D1, RB, p27, Ki67 and MSH2 in gallbladder carcinoma and its precursor lesions. Histol Histopathol. 2005;20:59–66.

    CAS  PubMed  Google Scholar 

  40. Dwivedi AN, et al. Gall bladder carcinoma: aggressive malignancy with protean loco-regional and distant spread. World J Gastroenterol. 2015;16:231–44.

    Google Scholar 

  41. Srivastava K, et al. Candidate gene studies in gallbladder cancer: a systemic review and meta-analysis. Mutat Res. 2011;728:67–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He XF, et al. Association between the CYP1A1 T3801C polymorphism and risk of cancer. Evidence from 268 case-control studies. Gene. 2013;534(2):324–44.

    Article  Google Scholar 

  43. Sharma KL, et al. Higher risk of matrix metalloproteinase (MMP-2, 7,9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants to gallbladder cancer. Liver Int. 2012;32:1278–86.

    Article  CAS  PubMed  Google Scholar 

  44. Nakamura H, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.

    Article  CAS  PubMed  Google Scholar 

  45. Burns MB, et al. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet. 2013;45:977–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Huch M, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. de Visser KE, et al. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24–37.

    Article  PubMed  Google Scholar 

  48. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mitelman F, et al. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233–45.

    Article  CAS  PubMed  Google Scholar 

  50. Ablain J, et al. The drug-induced degradation of oncoproteins: an unexpected Achilles’ heel of cancer cells? Cancer Discov. 2011;1:117–27.

    Article  CAS  PubMed  Google Scholar 

  51. Gu TL, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One. 2011;6:e15640–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Guagnano V, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov. 2012;2:1118–33.

    Article  CAS  PubMed  Google Scholar 

  53. Wu YM, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mittal B, Yadav S. Targeting the hedgehog pathway for gallbladder cancer therapy? Chin Clin Oncol. 2016;5:2–4.

    Article  PubMed  Google Scholar 

  55. Li M, et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet. 2014;46:872–6.

    Article  CAS  PubMed  Google Scholar 

  56. Phlip PA, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24:3069–74.

    Article  Google Scholar 

  57. Riener MO, et al. Rare PIK3CA hotspot mutations in carcinomas of biliary tract. Genes Chromosom Cancer. 2008;47:363–7.

    Article  CAS  PubMed  Google Scholar 

  58. Xu RF, et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother. 2011;65:22–6.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku, Kochi, 783-8505, Japan

    Kazuhiro Hanazaki, Masaya Munekage, Hiroyuki Kitagawa & Tsutomu Namikawa

  2. Departments of Hepatology and Gastroenterology, Kochi Medical School, Kochi University, Kochi, Japan

    Takuhiro Kosaki & Toshiji Saibara

Authors
  1. Kazuhiro Hanazaki
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  2. Masaya Munekage
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  3. Hiroyuki Kitagawa
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  4. Takuhiro Kosaki
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  5. Toshiji Saibara
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  6. Tsutomu Namikawa
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Corresponding author

Correspondence to Kazuhiro Hanazaki .

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Editors and Affiliations

  1. Department of Nanobio Drug Discovery, Kyoto University, Sakyo-ku, Kyoto, Japan

    Yutaka Shimada

  2. Department of Surgery, Jikei University School of Medicine, Minato-ku, Tokyo, Japan

    Katsuhiko Yanaga

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© 2018 Springer Nature Singapore Pte Ltd.

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Hanazaki, K., Munekage, M., Kitagawa, H., Kosaki, T., Saibara, T., Namikawa, T. (2018). Molecular Diagnosis and Targeting of Biliary Tract Cancer. In: Shimada, Y., Yanaga, K. (eds) Molecular Diagnosis and Targeting for Thoracic and Gastrointestinal Malignancy. Current Human Cell Research and Applications. Springer, Singapore. https://doi.org/10.1007/978-981-10-6469-2_7

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  • DOI: https://doi.org/10.1007/978-981-10-6469-2_7

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