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Association of HER2 gene amplification and tumor progression in early gastric cancer

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Abstract

Overexpression of human epidermal growth factor receptor 2 (HER2) protein in association with HER2 gene amplification is found in 7–34% of gastric cancers. In breast cancer, HER2 overexpression is a prognostic factor in advanced cases and is associated with tumor progression in ductal carcinoma in situ. However, the biological and clinical significance of HER2 status in early gastric cancer is unknown. Here, we aimed to examine the correlation between HER2 gene amplification and tumor progression in early gastric cancer. The HER2 status was evaluated in 149 lesions from 141 consecutive patients with early gastric cancer who underwent endoscopic resection by immunohistochemistry and dual color in situ hybridization. HER2 gene amplification was detected in 35 (23.5%) of 149 lesions, and of those, 26 cases (74.3%) showed intratumoral heterogeneity. HER2 gene amplification was found in noninvasive carcinoma, and there was a significant correlation between HER2 status and T factor (P = 0.0290). Our study demonstrated that HER2 gene amplification occurred during the early stages of gastric cancer and showed heterogeneity in several cases. HER2 gene amplification may be involved in tumor progression in early gastric cancer.

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References

  1. Bartkova J, Barnes DM, Millis RR, Gullick WJ (1990) Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinoma in situ. Hum Pathol 21:1164–1167

    Article  CAS  Google Scholar 

  2. Cassaro M, Rugge M, Tieppo C, Giacomelli L, Velo D, Nitti D, Farinati F (2007) Indefinite for non-invasive neoplasia lesions in gastric intestinal metaplasia: the immunophenotype. J Clin Pathol 60:615–621. https://doi.org/10.1136/jcp.2006.040386

    Article  PubMed  Google Scholar 

  3. Correa P, Piazuelo MB, Wilson KT (2010) Pathology of gastric intestinal metaplasia: clinical implications. Am J Gastroenterol 105:493–498. https://doi.org/10.1038/ajg.2009.728

    Article  PubMed  PubMed Central  Google Scholar 

  4. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486:537–540. https://doi.org/10.1038/nature11219

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Fassan M, Mastracci L, Grillo F, Zagonel V, Bruno S, Battaglia G, Pitto F, Nitti D, Celiento T, Zaninotto G, Fiocca R, Rugge M (2012) Early HER2 dysregulation in gastric and oesophageal carcinogenesis. Histopathology 61:769–776. https://doi.org/10.1111/j.1365-2559.2012.04272.x

    Article  PubMed  Google Scholar 

  6. Fassan M, Pizzi M, Farinati F, Nitti D, Zagonel V, Genta RM, Rugge M (2012) Lesions indefinite for intraepithelial neoplasia and OLGA staging for gastric atrophy. Am J Clin Pathol 137:727–732. https://doi.org/10.1309/AJCPEU41HTGXSJDQ

    Article  PubMed  Google Scholar 

  7. Garcia-Garcia E, Gomez-Martin C, Angulo B, Conde E, Suarez-Gauthier A, Adrados M, Perna C, Rodriguez-Peralto JL, Hidalgo M, Lopez-Rios F (2011) Hybridization for human epidermal growth factor receptor 2 testing in gastric carcinoma: a comparison of fluorescence in-situ hybridization with a novel fully automated dual-colour silver in-situ hybridization method. Histopathology 59:8–17. https://doi.org/10.1111/j.1365-2559.2011.03894.x

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, Ochiai A, Ruschoff J, Henkel T (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52:797–805. https://doi.org/10.1111/j.1365-2559.2008.03028.x

    Article  PubMed  CAS  Google Scholar 

  9. Kadota K, Suzuki K, Colovos C, Sima CS, Rusch VW, Travis WD, Adusumilli PS (2012) A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma. Mod Pathol 25:260–271. https://doi.org/10.1038/modpathol.2011.146

    Article  PubMed  CAS  Google Scholar 

  10. Kanayama K, Imai H, Yoneda M, Hirokawa YS, Shiraishi T (2016) Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: a comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. Cancer Sci 107:536–542. https://doi.org/10.1111/cas.12886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, Sakai Y (2013) HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer 16:84–93. https://doi.org/10.1007/s10120-012-0150-9

    Article  PubMed  CAS  Google Scholar 

  12. Kurozumi S, Padilla M, Kurosumi M, Matsumoto H, Inoue K, Horiguchi J, Takeyoshi I, Oyama T, Ranger-Moore J, Allred DC, Dennis E, Nitta H (2016) HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients. Breast Cancer Res Treat 158:99–111. https://doi.org/10.1007/s10549-016-3856-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lee S, de Boer WB, Fermoyle S, Platten M, Kumarasinghe MP (2011) Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections. Histopathology 59:832–840. https://doi.org/10.1111/j.1365-2559.2011.04017.x

    Article  PubMed  Google Scholar 

  14. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K (2014) Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514:54–58. https://doi.org/10.1038/nature13556

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Nakashima Y, Yao T, Hirahashi M, Aishima S, Kakeji Y, Maehara Y, Tsuneyoshi M (2011) Nuclear atypia grading score is a useful prognostic factor in papillary gastric adenocarcinoma. Histopathology 59:841–849. https://doi.org/10.1111/j.1365-2559.2011.04035.x

    Article  PubMed  Google Scholar 

  16. Roses RE, Paulson EC, Sharma A, Schueller JE, Nisenbaum H, Weinstein S, Fox KR, Zhang PJ, Czerniecki BJ (2009) HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiol Biomark Prev 18:1386–1389. https://doi.org/10.1158/1055-9965.EPI-08-1101

    Article  CAS  Google Scholar 

  17. Rugge M, de Boni M, Pennelli G, de Bona M, Giacomelli L, Fassan M, Basso D, Plebani M, Graham DY (2010) Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study. Aliment Pharmacol Ther 31:1104–1111. https://doi.org/10.1111/j.1365-2036.2010.04277.x

    Article  PubMed  CAS  Google Scholar 

  18. Rugge M, Pennelli G, Pilozzi E, Fassan M, Ingravallo G, Russo VM, Di Mario F (2011) Gastritis: the histology report. Dig Liver Dis 43(Suppl 4):S373–S384. https://doi.org/10.1016/s1590-8658(11)60593-8

    Article  PubMed  Google Scholar 

  19. Sawaki A, Ohashi Y, Omuro Y, Satoh T, Hamamoto Y, Boku N, Miyata Y, Takiuchi H, Yamaguchi K, Sasaki Y, Nishina T, Satoh A, Baba E, Tamura T, Abe T, Hatake K, Ohtsu A (2012) Efficacy of trastuzumab in Japanese patients with HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study. Gastric Cancer 15:313–322. https://doi.org/10.1007/s10120-011-0118-1

    Article  PubMed  CAS  Google Scholar 

  20. Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, Dixon MF, Fenoglio-Preiser CM, Flejou JF, Geboes K, Hattori T, Hirota T, Itabashi M, Iwafuchi M, Iwashita A, Kim YI, Kirchner T, Klimpfinger M, Koike M, Lauwers GY, Lewin KJ, Oberhuber G, Offner F, Price AB, Rubio CA, Shimizu M, Shimoda T, Sipponen P, Solcia E, Stolte M, Watanabe H, Yamabe H (2000) The Vienna classification of gastrointestinal epithelial neoplasia. Gut 47:251–255

    Article  CAS  Google Scholar 

  21. Seol H, Lee HJ, Choi Y, Lee HE, Kim YJ, Kim JH, Kang E, Kim SW, Park SY (2012) Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod Pathol 25:938–948. https://doi.org/10.1038/modpathol.2012.36

    Article  PubMed  CAS  Google Scholar 

  22. Silva TC, Leal MF, Calcagno DQ, de Souza CR, Khayat AS, dos Santos NP, Montenegro RC, Rabenhorst SH, Nascimento MQ, Assumpcao PP, de Arruda Cardoso Smith M, Burbano RR (2012) hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions. BMC Gastroenterol 12:85. https://doi.org/10.1186/1471-230x-12-85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D, Curtis C (2015) A Big Bang model of human colorectal tumor growth. Nat Genet 47:209–216. https://doi.org/10.1038/ng.3214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yoshida H, Yamamoto N, Taniguchi H, Oda I, Katai H, Kushima R, Tsuda H (2014) Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch 465:145–154. https://doi.org/10.1007/s00428-014-1597-3

    Article  PubMed  CAS  Google Scholar 

  25. Zheng Y (2010) Expression of p53, c-erbB-2 and Ki67 in intestinal metaplasia and gastric carcinoma. World J Gastroenterol 16:339–344. https://doi.org/10.3748/wjg.v16.i3.339

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

This work was supported in part by the Foundation for Promotion of Cancer Research in Japan.

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Authors and Affiliations

  1. Department of Clinical Nutrition, Suzuka University of Medical Science, 1001-1 Kishioka, Suzuka, Mie, 510-0293, Japan

    Kazuki Kanayama

  2. Department of Oncologic Pathology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Kazuki Kanayama, Eri Usugi, Taizo Shiraishi, Yoshifumi S. Hirokawa & Masatoshi Watanabe

  3. Pathology Division, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Hiroshi Imai

  4. Pathology Division, Kuwana City Medical Center, Kotobukicho, Kuwana-shi, Mie, 511-0061, Japan

    Taizo Shiraishi

Authors
  1. Kazuki Kanayama
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  2. Hiroshi Imai
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  3. Eri Usugi
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  4. Taizo Shiraishi
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  5. Yoshifumi S. Hirokawa
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  6. Masatoshi Watanabe
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Corresponding author

Correspondence to Hiroshi Imai.

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This study was approved by the ethics committee of Mie University Hospital (Tsu, Japan, approval no. 2746).

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The authors declare that they have no conflicts of interest.

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Kanayama, K., Imai, H., Usugi, E. et al. Association of HER2 gene amplification and tumor progression in early gastric cancer. Virchows Arch 473, 559–565 (2018). https://doi.org/10.1007/s00428-018-2433-y

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  • DOI: https://doi.org/10.1007/s00428-018-2433-y

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