Tumor Biology

, Volume 36, Issue 12, pp 9813–9821 | Cite as

Clinical and prognostic value of MET gene copy number gain and chromosome 7 polysomy in primary colorectal cancer patients

  • An Na Seo
  • Kyoung Un Park
  • Gheeyoung Choe
  • Woo Ho Kim
  • Duck-Woo Kim
  • Sung-Bum Kang
  • Hye Seung Lee
Research Article


We aimed to explore the clinical and prognostic influence of numeric alterations of MET gene copy number (GCN) and chromosome 7 (CEP7) CN in colorectal cancer (CRC) patients. MET GCN and CEP7 CN were investigated in tissue arrayed tumors from 170 CRC patients using silver in situ hybridization (SISH). MET GCN gain was defined as ≥4 copies of MET, and CEP7 polysomy was prespecified as ≥3 copies of CEP7. Additionally, MET messenger RNA (mRNA) transcription was evaluated using mRNA ISH and compared with MET GCN. MET GCN gain was observed in 14.7 % (25/170), which correlated with advanced stage (P = 0.037), presence of distant metastasis (P = 0.006), and short overall survival (OS) (P = 0.009). In contrast, CEP7 polysomy was found in 6.5 % (11/170), which was related to tumor location in the left colon (P = 0.027) and poor OS (P = 0.029). MET GCN positively correlated with CEP7 CN (R = 0.659, P < 0.001) and mRNA transcription (R = 0.239, P = 0.002). Of note, MET GCN gain and CEP7 polysomy were also associated with poor OS (P = 0.016 and P < 0.001, respectively) in stage II/III CRC patients (n = 123). In multivariate analysis, CEP7 polysomy was an independent prognostic factor for poor OS in all patients (P = 0.009; hazard ratio [HR], 2.220; 95 % confidence interval [CI], 1.233–3.997) and in stage II/III CRC patients (P < 0.001; HR, 20.781; 95 % CI, 4.600–93.882). MET GCN gain and CEP7 polysomy could predict a poor outcome in CRC patients, especially CEP7 polysomy has the most powerful prognostic impact in stage II/III CRC patients.


Colorectal cancer MET Chromosome 7 Silver in situ hybridization Copy number gain 



This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C1813).

Conflicts of interest


Supplementary material

13277_2015_3726_Fig3_ESM.gif (24 kb)
Fig. S1

Prognostic value of MET GCN and CEP7 CN status in 123 patients with stage II/III CRC. Kaplan-Meier survival curves of MET GCN gain (mean ≥4 MET copies/cell) for (A) overall survival (OS) and (B) progression-free survival (PFS). Kaplan-Meier survival curves of CEP7 polysomy (mean ≥3 CEP7 copies/cell) for (C) OS and (D) PFS (GIF 24 kb)

13277_2015_3726_MOESM1_ESM.tif (3.3 mb)
High resolution image (TIFF 3365 kb)
13277_2015_3726_MOESM2_ESM.docx (21 kb)
Supplementary Table S1 (DOCX 20 kb)


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi: 10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  2. 2.
    Chaput N, Svrcek M, Auperin A, Locher C, Drusch F, Malka D, et al. Tumor-infiltrating CD68+ and CD57+ cells predict patient outcome in stage II-III colorectal cancer. Br J Cancer. 2013;109(4):1013–22. doi: 10.1038/bjc.2013.362.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hari DM, Leung AM, Lee JH, Sim MS, Vuong B, Chiu CG, et al. AJCC cancer staging manual 7th edition criteria for colon cancer: do the complex modifications improve prognostic assessment? J Am Coll Surg. 2013;217(2):181–90. doi: 10.1016/j.jamcollsurg.2013.04.018.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15(7):2207–14. doi: 10.1158/1078-0432.ccr-08-1306.CrossRefPubMedGoogle Scholar
  5. 5.
    Go H, Jeon YK, Park HJ, Sung SW, Seo JW, Chung DH. High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol. 2010;5(3):305–13. doi: 10.1097/JTO.0b013e3181ce3d1d.CrossRefPubMedGoogle Scholar
  6. 6.
    Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res. 2006;12(12):3657–60. doi: 10.1158/1078-0432.ccr-06-0818.CrossRefPubMedGoogle Scholar
  7. 7.
    Lee J, Seo JW, Jun HJ, Ki CS, Park SH, Park YS, et al. Impact of MET amplification on gastric cancer: possible roles as a novel prognostic marker and a potential therapeutic target. Oncol Rep. 2011;25(6):1517–24. doi: 10.3892/or.2011.1219.PubMedGoogle Scholar
  8. 8.
    Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27(10):1667–74. doi: 10.1200/jco.2008.19.1635.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tanaka A, Sueoka-Aragane N, Nakamura T, Takeda Y, Mitsuoka M, Yamasaki F, et al. Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients. Lung Cancer. 2012;75(1):89–94. doi: 10.1016/j.lungcan.2011.06.004.CrossRefPubMedGoogle Scholar
  10. 10.
    Jin Y, Sun PL, Kim H, Seo AN, Jheon S, Lee CT, et al. MET gene copy number gain is an independent poor prognostic marker in Korean stage I lung adenocarcinomas. Ann Surg Oncol. 2014;21(2):621–8. doi: 10.1245/s10434-013-3355-1.CrossRefPubMedGoogle Scholar
  11. 11.
    Lee HE, Kim MA, Lee HS, Jung EJ, Yang HK, Lee BL, et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer. 2012;107(2):325–33. doi: 10.1038/bjc.2012.237.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011;29(10):1271–9. doi: 10.1200/jco.2010.31.0367.CrossRefPubMedGoogle Scholar
  13. 13.
    Peters S, Adjei AA. MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol. 2012;9(6):314–26. doi: 10.1038/nrclinonc.2012.71.CrossRefPubMedGoogle Scholar
  14. 14.
    Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M, et al. c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res. 2003;9(4):1480–8.PubMedGoogle Scholar
  15. 15.
    Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008;265(2):258–69. doi: 10.1016/j.canlet.2008.02.049.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Edge SB, Byrd DR, Compton C, Fritz A, Greene F, Trotti A. American joint committee on cancer staging manual. American Joint Committee on Cancer Staging Manual. 2010.Google Scholar
  17. 17.
    Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park do J, et al. Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res. 2007;13(14):4154–63. doi: 10.1158/1078-0432.ccr-07-0173.CrossRefPubMedGoogle Scholar
  18. 18.
    Voravud N, Shin DM, Ro JY, Lee JS, Hong WK, Hittelman WN. Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. Cancer Res. 1993;53(12):2874–83.PubMedGoogle Scholar
  19. 19.
    Ha SY, Lee J, Kang SY, Do IG, Ahn S, Park JO, et al. MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas. Mod Pathol. 2013. doi: 10.1038/modpathol.2013.108.PubMedGoogle Scholar
  20. 20.
    Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn. 2012;14(1):22–9. doi: 10.1016/j.jmoldx.2011.08.002.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim MA, Jung JE, Lee HE, Yang HK, Kim WH. In situ analysis of HER2 mRNA in gastric carcinoma: comparison with fluorescence in situ hybridization, dual-color silver in situ hybridization, and immunohistochemistry. Hum Pathol. 2013;44(4):487–94. doi: 10.1016/j.humpath.2012.06.022.CrossRefPubMedGoogle Scholar
  22. 22.
    Choi J, Lee HE, Kim MA, Jang BG, Lee HS, Kim WH. Analysis of MET mRNA expression in gastric cancers using RNA in situ hybridization assay: its clinical implication and comparison with immunohistochemistry and silver in situ hybridization. PLoS One. 2014;9(11), e111658. doi: 10.1371/journal.pone.0111658.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Oh JR, Kim DW, Lee HS, Lee HE, Lee SM, Jang JH, et al. Microsatellite instability testing in Korean patients with colorectal cancer. Fam Cancer. 2012;11(3):459–66. doi: 10.1007/s10689-012-9536-4.CrossRefPubMedGoogle Scholar
  24. 24.
    Kim JH, Bae JM, Kim KJ, Rhee YY, Kim Y, Cho NY, et al. Differential features of microsatellite-unstable colorectal carcinomas depending on EPCAM expression status. Korean J Pathol. 2014;48(4):276–82. doi: 10.4132/KoreanJPathol.2014.48.4.276.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Seo AN, Kwak Y, Kim DW, Kang SB, Choe G, Kim WH, et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One. 2014;9(5), e98528. doi: 10.1371/journal.pone.0098528.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Guo B, Cen H, Tan X, Liu W, Ke Q. Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures. PLoS One. 2014;9(6), e99399. doi: 10.1371/journal.pone.0099399.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. doi: 10.1038/nature11252.CrossRefGoogle Scholar
  28. 28.
    Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F, et al. Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci U S A. 2009;106(17):7131–6. doi: 10.1073/pnas.0902232106.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jardim DL, Tang C, Gagliato Dde M, Falchook GS, Hess K, Janku F, et al. Analysis of 1,115 patients tested for MET amplification and therapy response in the MD Anderson Phase I Clinic. Clin Cancer Res. 2014;20(24):6336–45. doi: 10.1158/1078-0432.ccr-14-1293.CrossRefPubMedGoogle Scholar
  30. 30.
    Gordon MS, Sweeney CS, Mendelson DS, Eckhardt SG, Anderson A, Beaupre DM, et al. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors. Clin Cancer Res. 2010;16(2):699–710. doi: 10.1158/1078-0432.ccr-09-1365.CrossRefPubMedGoogle Scholar
  31. 31.
    Katayama R, Aoyama A, Yamori T, Qi J, Oh-hara T, Song Y, et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 2013;73(10):3087–96. doi: 10.1158/0008-5472.can-12-3256.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res. 2006;12(20 Pt 1):6144–52. doi: 10.1158/1078-0432.ccr-05-1418.CrossRefPubMedGoogle Scholar
  33. 33.
    Inno A, Di Salvatore M, Cenci T, Martini M, Orlandi A, Strippoli A, et al. Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? Clin Colorectal Cancer. 2011;10(4):325–32. doi: 10.1016/j.clcc.2011.03.028.CrossRefPubMedGoogle Scholar
  34. 34.
    Abou-Bakr AA, Elbasmi A. c-MET overexpression as a prognostic biomarker in colorectal adenocarcinoma. Gulf J Oncolog. 2013;1(14):28–34.PubMedGoogle Scholar
  35. 35.
    Garouniatis A, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumor progression, metastasis, patient survival and receptor crosstalk. Int J Color Dis. 2013;28(1):9–18. doi: 10.1007/s00384-012-1520-9.CrossRefGoogle Scholar
  36. 36.
    Gao H, Guan M, Sun Z, Bai C. High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis. Tumor Biol. 2015;36(2):515–20. doi: 10.1007/s13277-014-2659-5.CrossRefGoogle Scholar
  37. 37.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643–55. doi: 10.1093/jnci/dji112.CrossRefPubMedGoogle Scholar
  38. 38.
    Diep CB, Parada LA, Teixeira MR, Eknaes M, Nesland JM, Johansson B, et al. Genetic profiling of colorectal cancer liver metastases by combined comparative genomic hybridization and G-banding analysis. Genes Chromosomes Cancer. 2003;36(2):189–97. doi: 10.1002/gcc.10162.CrossRefPubMedGoogle Scholar
  39. 39.
    Toffalorio F, de Marinis F, Conforti F, Spitaleri G, Catania C, Noberasco C, et al. Erlotinib efficacy in NSCLC patients with high polysomy of chromosome 7 and EGFR/KRas wild-type tumors. J Thorac Oncol. 2015;10(2):392–6. doi: 10.1097/jto.0000000000000355.CrossRefPubMedGoogle Scholar
  40. 40.
    Li YH, Wang F, Shen L, Deng YM, Shao Q, Feng F, et al. EGFR fluorescence in situ hybridization pattern of chromosome 7 disomy predicts resistance to cetuximab in KRAS wild-type metastatic colorectal cancer patients. Clin Cancer Res. 2011;17(2):382–90. doi: 10.1158/1078-0432.ccr-10-0208.CrossRefPubMedGoogle Scholar
  41. 41.
    Seo AN, Jin Y, Lee HJ, Sun PL, Kim H, Jheon S, et al. FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer. Virchows Arch. 2014;465(5):547–58. doi: 10.1007/s00428-014-1634-2.CrossRefPubMedGoogle Scholar
  42. 42.
    Hsu FD, Nielsen TO, Alkushi A, Dupuis B, Huntsman D, Liu CL, et al. Tissue microarrays are an effective quality assurance tool for diagnostic immunohistochemistry. Mod Pathol. 2002;15(12):1374–80. doi: 10.1097/ Scholar
  43. 43.
    Voduc D, Kenney C, Nielsen TO. Tissue microarrays in clinical oncology. Semin Radiat Oncol. 2008;18(2):89–97. doi: 10.1016/j.semradonc.2007.10.006.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • An Na Seo
    • 1
  • Kyoung Un Park
    • 2
  • Gheeyoung Choe
    • 3
    • 4
  • Woo Ho Kim
    • 4
  • Duck-Woo Kim
    • 5
  • Sung-Bum Kang
    • 5
  • Hye Seung Lee
    • 3
  1. 1.Department of Pathology, Kyungpook National University Medical CenterKyungpook National University School of MedicineDaeguRepublic of Korea
  2. 2.Department of Laboratory MedicineSeoul National University Bundang HospitalSeongnam-siRepublic of Korea
  3. 3.Department of PathologySeoul National University Bundang HospitalBundang-gu, Seongnam-siRepublic of Korea
  4. 4.Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
  5. 5.Department of SurgerySeoul National University Bundang HospitalSeongnam-siRepublic of Korea

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