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Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas

Virchows Archiv volume 477, pages 33–45 (2020)Cite this article

Abstract

Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting ROS1, ALK, MET, and HER2 alterations are currently evaluated in clinical trials. We assessed ROS1 and ALK translocations/amplifications as well as MET and HER2 amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (n = 194). By FISH, we detected targetable alterations in 5.2% of cases (n = 10): HER2 and MET amplifications were found in 4.1% (n = 8) and 1.0% (n = 2), respectively. The HER2-amplified cases were mostly gallbladder adenocarcinomas (n = 5). The MET- and HER2-amplified cases were all positive by IHC. Fourteen cases without MET amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in HER2-amplified cases. We detected no ALK or ROS1 translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of ROS1 gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of HER2 amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen MET amplification. Contrary to initial publications, ROS1 rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.

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References

  1. Groot Koerkamp B, Fong Y (2014) Outcomes in biliary malignancy. J Surg Oncol 110(5):585–591. https://doi.org/10.1002/jso.23762

    Article  PubMed  Google Scholar 

  2. Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24(2):115–125. https://doi.org/10.1055/s-2004-828889

    Article  PubMed  Google Scholar 

  3. DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ, Schulick RD (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245(5):755–762. https://doi.org/10.1097/01.sla.0000251366.62632.d3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Abdel-Rahman O, Elsayed Z, Elhalawani H (2018) Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. Cochrane Database Syst Rev 4:Cd011746. https://doi.org/10.1002/14651858.CD011746.pub2

    Article  PubMed  Google Scholar 

  5. Rizvi S, Gores GJ (2017) Emerging molecular therapeutic targets for cholangiocarcinoma. J Hepatol 67(3):632–644. https://doi.org/10.1016/j.jhep.2017.03.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, Wang Y, Deng G, Zhu L, Tan Z, Hu Y, Wu C, Nardone J, MacNeill J, Ren J, Reeves C, Innocenti G, Norris B, Yuan J, Yu J, Haack H, Shen B, Peng C, Li H, Zhou X, Liu X, Rush J, Comb MJ (2011) Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 6(1):e15640. https://doi.org/10.1371/journal.pone.0015640

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Peraldo Neia C, Cavalloni G, Balsamo A, Venesio T, Napoli F, Sassi F, Martin V, Frattini M, Aglietta M, Leone F (2014) Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR. Genes Chromosom Cancer 53(12):1033–1040. https://doi.org/10.1002/gcc.22212

    CAS  Article  PubMed  Google Scholar 

  8. Lim SM, Yoo JE, Lim KH, Meng Tai DW, Cho BC, Park YN (2017) Rare incidence of ROS1 rearrangement in cholangiocarcinoma. Cancer Res Treat 49(1):185–192. https://doi.org/10.4143/crt.2015.497

    CAS  Article  PubMed  Google Scholar 

  9. Chiang NJ, Hsu C, Chen JS, Tsou HH, Shen YY, Chao Y, Chen MH, Yeh TS, Shan YS, Huang SF, Chen LT (2016) Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer. Sci Rep 6:25369. https://doi.org/10.1038/srep25369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA, Vasmatzis G, Murphy SJ, McWilliams RR, Hart SN, Halling KC, Roberts LR, Gores GJ, Couch FJ, Zhang L, Borad MJ, Kipp BR (2014) Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 45(8):1630–1638. https://doi.org/10.1016/j.humpath.2014.03.014

    CAS  Article  PubMed  Google Scholar 

  11. Voss JS, Holtegaard LM, Kerr SE, Fritcher EG, Roberts LR, Gores GJ, Zhang J, Highsmith WE, Halling KC, Kipp BR (2013) Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol 44(7):1216–1222. https://doi.org/10.1016/j.humpath.2012.11.006

    CAS  Article  PubMed  Google Scholar 

  12. Albrecht T, Rausch M, Roessler S, Geissler V, Albrecht M, Halske C, Seifert C, Renner M, Singer S, Mehrabi A, Vogel MN, Pathil-Warth A, Busch E, Kohler B, Rupp C, Weiss KH, Springfeld C, Rocken C, Schirmacher P, Goeppert B (2019) HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma. Virchows Archiv. https://doi.org/10.1007/s00428-019-02706-6

  13. Albrecht T, Rausch M, Rossler S, Albrecht M, Braun JD, Geissler V, Mehrabi A, Vogel MN, Pathil-Warth A, Mechtersheimer G, Renner M, Rupp C, Weiss KH, Busch E, Kohler B, Springfeld C, Schirmacher P, Goeppert B (2019) HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis. BMC Cancer 19(1):1191. https://doi.org/10.1186/s12885-019-6320-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Javle M, Bekaii-Saab T, Jain A, Wang Y, Kelley RK, Wang K, Kang HC, Catenacci D, Ali S, Krishnan S, Ahn D, Bocobo AG, Zuo M, Kaseb A, Miller V, Stephens PJ, Meric-Bernstam F, Shroff R, Ross J (2016) Biliary cancer: utility of next-generation sequencing for clinical management. Cancer 122(24):3838–3847. https://doi.org/10.1002/cncr.30254

    CAS  Article  PubMed  Google Scholar 

  15. Kim Y, Bang SS, Jee S, Park S, Shin SJ, Jang K (2019) Prevalence and clinicopathological significance of MET overexpression and gene amplification in patients with gallbladder carcinoma. Cancer Res Treat 52:481–491. https://doi.org/10.4143/crt.2019.370

    Article  PubMed  PubMed Central  Google Scholar 

  16. Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A (2005) Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 206(3):356–365. https://doi.org/10.1002/path.1779

    CAS  Article  PubMed  Google Scholar 

  17. Shafizadeh N, Grenert JP, Sahai V, Kakar S (2010) Epidermal growth factor receptor and HER-2/neu status by immunohistochemistry and fluorescence in situ hybridization in adenocarcinomas of the biliary tree and gallbladder. Hum Pathol 41(4):485–492. https://doi.org/10.1016/j.humpath.2009.10.002

    CAS  Article  PubMed  Google Scholar 

  18. Yoshida H, Shimada K, Kosuge T, Hiraoka N (2016) A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status. Virchows Archiv 468(4):431–439. https://doi.org/10.1007/s00428-015-1898-1

    CAS  Article  PubMed  Google Scholar 

  19. Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, Hirohashi S, Shibata T (2008) Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer 98(2):418–425. https://doi.org/10.1038/sj.bjc.6604129

    CAS  Article  PubMed  Google Scholar 

  20. Pellino A, Loupakis F, Cadamuro M, Dadduzio V, Fassan M, Guido M, Cillo U, Indraccolo S, Fabris L (2018) Precision medicine in cholangiocarcinoma. Transl Gastroenterol Hepatol 3:40. https://doi.org/10.21037/tgh.2018.07.02

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wiggers JK, Ruys AT, Groot Koerkamp B, Beuers U, ten Kate FJ, van Gulik TM (2014) Differences in immunohistochemical biomarkers between intra- and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Gastroenterol Hepatol 29(8):1582–1594. https://doi.org/10.1111/jgh.12620

    Article  PubMed  Google Scholar 

  22. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010. https://doi.org/10.1038/ng.3375

    CAS  Article  PubMed  Google Scholar 

  23. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, Lind GE, Folseraas T, Forbes SJ, Fouassier L, Geier A, Calvisi DF, Mertens JC, Trauner M, Benedetti A, Maroni L, Vaquero J, Macias RI, Raggi C, Perugorria MJ, Gaudio E, Boberg KM, Marin JJ, Alvaro D (2016) Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 13(5):261–280. https://doi.org/10.1038/nrgastro.2016.51

    Article  PubMed  Google Scholar 

  24. Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, Carpino G (2019) Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int 39(Suppl 1):7–18. https://doi.org/10.1111/liv.14093

  25. Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM (2014) Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 27(8):1163–1173. https://doi.org/10.1038/modpathol.2013.241

    CAS  Article  PubMed  Google Scholar 

  26. Paradis V, Fukayama M, Park YN, Schirmacher P (2019) Tumours of the liver and intrahepatic bile ducts. Lyon (France); International Agency for Research on Cancer; WHO classification of tumours: digestive system tumours, 5th edn. World Health Organization, Geneva, pp 216–264. http://publications.iarc.fr/579

  27. WHO Classification of Tumours Edittorial Board (2019) Digestive system tumours, 5th edn. IARC, Lyon

    Google Scholar 

  28. Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, Penault-Llorca F, Nagelmeier I, Schlake W, Hofler H, Kreipe HH (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Archiv 457(3):299–307. https://doi.org/10.1007/s00428-010-0952-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, Raja R, Mohan S, Patel R, Desai R, Fu L, Do A, Parab V, Xia X, Januario T, Louie SG, Filvaroff E, Shames DS, Wistuba I, Lipkind M, Huang J, Lazarov M, Ramakrishnan V, Amler L, Phan SC, Patel P, Peterson A, Yauch RL (2014) Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib ± onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res 20(17):4488–4498. https://doi.org/10.1158/1078-0432.ccr-13-1836

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Peretti U, Ferrara R, Pilotto S, Kinspergher S, Caccese M, Santo A, Brunelli M, Calio A, Carbognin L, Sperduti I, Garassino M, Chilosi M, Scarpa A, Tortora G, Bria E (2016) ALK gene copy number gains in non-small-cell lung cancer: prognostic impact and clinico-pathological correlations. Respir Res 17(1):105. https://doi.org/10.1186/s12931-016-0422-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Zasadil LM, Britigan EM, Weaver BA (2013) 2n or not 2n: aneuploidy, polyploidy and chromosomal instability in primary and tumor cells. Semin Cell Dev Biol 24(4):370–379. https://doi.org/10.1016/j.semcdb.2013.02.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR (2008) Defining ‘chromosomal instability’. Trends Genet 24(2):64–69. https://doi.org/10.1016/j.tig.2007.11.006

    CAS  Article  PubMed  Google Scholar 

  33. Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB 3rd, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA (2017) HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 35(4):446–464. https://doi.org/10.1200/jco.2016.69.4836

    CAS  Article  PubMed  Google Scholar 

  34. Xu Y, Peng Z, Li Z, Lu M, Gao J, Li Y, Li Y, Shen L (2015) Expression and clinical significance of c-Met in advanced esophageal squamous cell carcinoma. BMC Cancer 15:6. https://doi.org/10.1186/s12885-014-1001-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Roa I, de Toro G, Schalper K, de Aretxabala X, Churi C, Javle M (2014) Overexpression of the HER2/neu gene: a new therapeutic possibility for patients with advanced gallbladder cancer. Gastrointest Cancer Res 7(2):42–48

    PubMed  PubMed Central  Google Scholar 

  36. Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R (2015) HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev 34(1):157–164. https://doi.org/10.1007/s10555-015-9552-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J, Tabak B, Peix J, Sole M, Tovar V, Alsinet C, Cornella H, Klotzle B, Fan JB, Cotsoglou C, Thung SN, Fuster J, Waxman S, Garcia-Valdecasas JC, Bruix J, Schwartz ME, Beroukhim R, Mazzaferro V, Llovet JM (2013) Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144(4):829–840. https://doi.org/10.1053/j.gastro.2013.01.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Rijken AM, Hu J, Perlman EJ, Morsberger LA, Long P, Kern SE, Hruban RH, Yeo CJ, Griffin CA (1999) Genomic alterations in distal bile duct carcinoma by comparative genomic hybridization and karyotype analysis. Genes Chromosom Cancer 26(3):185–191

    CAS  Article  PubMed  Google Scholar 

  39. Klimstra D, Lam A, Paradis V, Schirmacher P (2019) Tumours of the gallbladder and extrahepatic bile ducts WHO classification of tumours: digestive system tumours. Lyon (France); International Agency for Research on Cancer; WHO classification of tumours: digestive system tumours, 5th edn. World Health Organization, Geneva, pp 266–294. http://publications.iarc.fr/579

  40. Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J, Zuo M, Zinner R, Hong D, Meric-Bernstam F, Janku F, Crane CH, Mishra L, Vauthey JN, Wolff RA, Mills G, Javle M (2014) Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One 9(12):e115383. https://doi.org/10.1371/journal.pone.0115383

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Potapova TA, Zhu J, Li R (2013) Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev 32(3–4):377–389. https://doi.org/10.1007/s10555-013-9436-6

    Article  PubMed  Google Scholar 

  42. Garrido-Ramos MA (2017) Satellite DNA: an evolving topic. Genes (Basel) 8(9). https://doi.org/10.3390/genes8090230

  43. Eymery A, Horard B, El Atifi-Borel M, Fourel G, Berger F, Vitte AL, Van den Broeck A, Brambilla E, Fournier A, Callanan M, Gazzeri S, Khochbin S, Rousseaux S, Gilson E, Vourc'h C (2009) A transcriptomic analysis of human centromeric and pericentric sequences in normal and tumor cells. Nucleic Acids Res 37(19):6340–6354. https://doi.org/10.1093/nar/gkp639

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Ichida K, Suzuki K, Fukui T, Takayama Y, Kakizawa N, Watanabe F, Ishikawa H, Muto Y, Kato T, Saito M, Futsuhara K, Miyakura Y, Noda H, Ohmori T, Konishi F, Rikiyama T (2018) Overexpression of satellite alpha transcripts leads to chromosomal instability via segregation errors at specific chromosomes. Int J Oncol. https://doi.org/10.3892/ijo.2018.4321

  45. McNulty SM, Sullivan BA (2018) Alpha satellite. DNA Biol 26(3):115–138. https://doi.org/10.1007/s10577-018-9582-3

    CAS  Article  Google Scholar 

  46. Vaquero J, Lobe C, Fouassier L (2018) Unveiling resistance mechanisms to EGFR inhibitors in cholangiocarcinoma. Oncotarget 9(99):37274–37275. https://doi.org/10.18632/oncotarget.26403

    Article  PubMed  PubMed Central  Google Scholar 

  47. Fouassier L, Marzioni M, Afonso MB, Dooley S, Gaston K, Giannelli G, Rodrigues CMP, Lozano E, Mancarella S, Segatto O, Vaquero J, Marin JJG, Coulouarn C (2019) Signalling networks in cholangiocarcinoma: molecular pathogenesis, targeted therapies and drug resistance. Liver Int 39(Suppl 1):43–62. https://doi.org/10.1111/liv.14102

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Acknowledgments

We thank Sylvie Dumont and Fatiha Merabtene (“Plateforme d’Histomorphologie St-Antoine,” Sorbonne Université, UMS30 LUMIC) for technical assistance.

Funding

This study was funded by the academic grant from AFEF (AAP 2014-R14192DD).

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Author notes

  1. Pascale Cervera and Dominique Wendum contributed equally to this work.

Affiliations

  1. Service d’Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint Antoine, 75012, Paris, France

    Jeremy Augustin, Caroline Gabignon, Aurélie Scriva, Jean-François Fléjou, Pascale Cervera & Dominique Wendum

  2. INSERM UMR_S 938, Centre de Recherche Saint-Antoine (CRSA), Faculté de Médecine Sorbonne Université, 75012, Paris, France

    Jeremy Augustin, Laëtitia Menu, Claire Calmel, Olivier Scatton, François Paye, Jean-François Fléjou, Françoise Praz, Pascale Cervera & Dominique Wendum

  3. Service de Chirurgie Hépato-Biliaire et Transplantation Hépatique, AP-HP, Hôpital Saint Antoine, 75012, Paris, France

    Olivier Scatton

  4. Service de Chirurgie Digestive, AP-HP, Hôpital Saint Antoine, 75012, Paris, France

    François Paye

  5. Centre National de la Recherche Scientifique (CNRS), Paris, France

    Françoise Praz

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  1. Jeremy Augustin
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Contributions

Dominique Wendum and Pascale Cervera conceived and designed the study. Jeremy Augustin, Pascale Cervera, and Dominique Wendum wrote the manuscript. Pascale Cervera and Jeremy Augustin analyzed in situ hybridization data. Jeremy Augustin, Pascale Cervera, and Dominique Wendum analyzed immunohistochemical data. Françoise Praz supervised RT-PCR and Western blotting experiments. Jean-François Fléjou, Olivier Scatton, François Paye, and Françoise Praz edited and reviewed the manuscript. Caroline Gabignon, Aurélie Scriva, Claire Calmel, and Laetitia Menu performed and interpreted experiments and reviewed the manuscript. All authors gave final approval for publication. Jeremy Augustin, Pascale Cervera, and Dominique Wendum take full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

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Correspondence to Pascale Cervera.

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Augustin, J., Gabignon, C., Scriva, A. et al. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas. Virchows Arch 477, 33–45 (2020). https://doi.org/10.1007/s00428-020-02822-8

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Keywords

  • Biliary tract adenocarcinoma
  • HER2
  • MET
  • ROS1
  • Fluorescent in situ hybridization
  • Immunohistochemistry