Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival

Abstract

Several classification systems have been described for stratifying patients with gastric carcinoma (GC). However, their prognostic value is low, and there is an urgent need for identification of molecular markers and development of new classifications. Retrospective study of 206 cases of GC diagnosed and surgically resected in our hospital between 2000 and 2017. Clinicopathological features of all cases were assessed and tissue microarrays were constructed for immunohistochemical (IHC) study. Patients were stratified based on IHC results. Mean patient age was 71 years and most patients were male (54.6%). Most tumors were located in the gastric antrum and body, and they were mostly fungoid or ulcerative lesions. GC were mainly intestinal-type tumors and 60.3% were diagnosed at pT3. 56.2% of patients showed recurrences and 29.4% died due to GC. According to our IHC classification, 23.5% of tumors showed microsatellite instability, 6% were E-cadherin negative, 53.5% were stable-p53 not overexpressed, and 17% were stable with p53 overexpression. IHC classification was significantly correlated with patient gender, gross morphology, Laurén classification, tumor necrosis, perineural infiltration, type of leading edge, and patient outcome. Multivariate analysis showed that IHC subtype was significantly and independently associated with overall survival, together with clinical symptoms, signet cell phenotype, tumor grade and vessel invasion. The application of IHC classifications based on molecular biomarkers in clinical practice can aid in the stratification of GC patients. More studies are needed to evaluate the reproducibility and clinical significance of these classifications.

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References

  1. 1.

    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403

    CAS  Article  Google Scholar 

  2. 2.

    Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D et al (2016) Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27:v38–v49

    CAS  Article  Google Scholar 

  3. 3.

    Laurén P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49

    Article  Google Scholar 

  4. 4.

    Bosman F, Carneiro F, Hruban RH (2010) WHO classification of tumors of the digestive system, 4th edn. IARC, Lyon

    Google Scholar 

  5. 5.

    Goseki N, Takizawa T, Koike M (1992) Differences in the mode of the extension of gastric cancer classified by histological type: new histological classification of gastric carcinoma. Gut 33:606–612

    CAS  Article  Google Scholar 

  6. 6.

    Ming SC (1977) Gastric carcinoma. A pathobiological classification. Cancer 39:2475–2485

    CAS  Article  Google Scholar 

  7. 7.

    Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J et al (2011) Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 141:476–485.e11

    Article  Google Scholar 

  8. 8.

    Zhou Y-Y, Kang Y-T, Chen C, Xu F-F, Wang H-N, Jin R (2018) Combination of TNM staging and pathway based risk score models in patients with gastric cancer. J Cell Biochem 119:3608–3617

    CAS  Article  Google Scholar 

  9. 9.

    Cristescu R, Lee J, Nebozhyn M, Kim K-M, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, Ye XS, Do IG, Liu S, Gong L, Fu J, Jin JG, Choi MG, Sohn TS, Lee JH, Bae JM, Kim ST, Park SH, Sohn I, Jung SH, Tan P, Chen R, Hardwick J, Kang WK, Ayers M, Hongyue D, Reinhard C, Loboda A, Kim S, Aggarwal A (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21:449–456

    CAS  Article  Google Scholar 

  10. 10.

    Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih IM, Kurman RJ (2011) Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol 24:1248–1253

    CAS  Article  Google Scholar 

  11. 11.

    Bellini MF, Cadamuro ACT, Succi M, Proença MA, Silva AE (2012) Alterations of the TP53 gene in gastric and esophageal carcinogenesis. J Biomed Biotechnol 2012:891961

    Article  Google Scholar 

  12. 12.

    Cole AJ, Dwight T, Gill AJ, Dickson K-A, Zhu Y, Clarkson A, Gard GB, Maidens J, Valmadre S, Clifton-Bligh R, Marsh DJ (2016) Assessing mutant p53 in primary high-grade serous ovarian cancer using immunohistochemistry and massively parallel sequencing. Sci Rep 6:26191

    CAS  Article  Google Scholar 

  13. 13.

    Taylor D, Koch WM, Zahurak M, Shah K, Sidransky D, Westra WH (1999) Immunohistochemical detection of p53 protein accumulation in head and neck cancer: correlation with p53 gene alterations. Hum Pathol 30:1221–1225

    CAS  Article  Google Scholar 

  14. 14.

    Murnyák B, Horobágyi T (2016) Immunohistochemical correlates of TP53 somatic mutations in cancer. Oncotarget 7:64910–64920

    Article  Google Scholar 

  15. 15.

    Kuan S-F, Ren B, Brand R, Dudley B, Pai RK (2017) Neoadjuvant therapy in microsatellite-stable colorectal carcinoma induces concomitant loss of MSH6 and Ki-67 expression. Hum Pathol 63:33–39

    CAS  Article  Google Scholar 

  16. 16.

    Bass AJ, Thorsson V, Shmulevich I, Reynolds SM, Miller M, Bernard B, Hinoue T, Laird PW, Curtis C, Shen H, Weisenberger DJ, Schultz N, Shen R, Weinhold N, Kelsen DP, Bowlby R, Chu A, Kasaian K, Mungall AJ, Gordon Robertson A, Sipahimalani P, Cherniack A, Getz G, Liu Y, Noble MS, Pedamallu C, Sougnez C, Taylor-Weiner A, Akbani R, Lee JS, Liu W, Mills GB, Yang D, Zhang W, Pantazi A, Parfenov M, Gulley M, Blanca Piazuelo M, Schneider BG, Kim J, Boussioutas A, Sheth M, Demchok JA, Rabkin CS, Willis JE, Ng S, Garman K, Beer DG, Pennathur A, Raphael BJ, Wu HT, Odze R, Kim HK, Bowen J, Leraas KM, Lichtenberg TM, Weaver S, McLellan M, Wiznerowicz M, Sakai R, Getz G, Sougnez C, Lawrence MS, Cibulskis K, Lichtenstein L, Fisher S, Gabriel SB, Lander ES, Ding L, Niu B, Ally A, Balasundaram M, Birol I, Bowlby R, Brooks D, Butterfield YSN, Carlsen R, Chu A, Chu J, Chuah E, Chun HJE, Clarke A, Dhalla N, Guin R, Holt RA, Jones SJM, Kasaian K, Lee D, Li HA, Lim E, Ma Y, Marra MA, Mayo M, Moore RA, Mungall AJ, Mungall KL, Ming Nip K, Gordon Robertson A, Schein JE, Sipahimalani P, Tam A, Thiessen N, Beroukhim R, Carter SL, Cherniack AD, Cho J, Cibulskis K, DiCara D, Frazer S, Fisher S, Gabriel SB, Gehlenborg N, Heiman DI, Jung J, Kim J, Lander ES, Lawrence MS, Lichtenstein L, Lin P, Meyerson M, Ojesina AI, Sekhar Pedamallu C, Saksena G, Schumacher SE, Sougnez C, Stojanov P, Tabak B, Taylor-Weiner A, Voet D, Rosenberg M, Zack TI, Zhang H, Zou L, Protopopov A, Santoso N, Parfenov M, Lee S, Zhang J, Mahadeshwar HS, Tang J, Ren X, Seth S, Yang L, Xu AW, Song X, Pantazi A, Xi R, Bristow CA, Hadjipanayis A, Seidman J, Chin L, Park PJ, Kucherlapati R, Akbani R, Ling S, Liu W, Rao A, Weinstein JN, Kim SB, Lee JS, Lu Y, Mills G, Laird PW, Hinoue T, Weisenberger DJ, Bootwalla MS, Lai PH, Shen H, Triche Jr T, van den Berg DJ, Baylin SB, Herman JG, Getz G, Chin L, Liu Y, Murray BA, Noble MS, Arman Askoy B, Ciriello G, Dresdner G, Gao J, Gross B, Jacobsen A, Lee W, Ramirez R, Sander C, Schultz N, Senbabaoglu Y, Sinha R, Onur Sumer S, Sun Y, Weinhold N, Thorsson V, Bernard B, Iype L, Kramer RW, Kreisberg R, Miller M, Reynolds SM, Rovira H, Tasman N, Shmulevich I, Ng S, Haussler D, Stuart JM, Akbani R, Ling S, Liu W, Rao A, Weinstein JN, Verhaak RGW, Mills GB, Leiserson MDM, Raphael BJ, Wu HT, Taylor BS, Black AD, Bowen J, Ann Carney J, Gastier-Foster JM, Helsel C, Leraas KM, Lichtenberg TM, McAllister C, Ramirez NC, Tabler TR, Wise L, Zmuda E, Penny R, Crain D, Gardner J, Lau K, Curely E, Mallery D, Morris S, Paulauskis J, Shelton T, Shelton C, Sherman M, Benz C, Lee JH, Fedosenko K, Manikhas G, Potapova O, Voronina O, Belyaev D, Dolzhansky O, Kimryn Rathmell W, Brzezinski J, Ibbs M, Korski K, Kycler W, Łaźniak R, Leporowska E, Mackiewicz A, Murawa D, Murawa P, Spychała A, Suchorska WM, Tatka H, Teresiak M, Wiznerowicz M, Abdel-Misih R, Bennett J, Brown J, Iacocca M, Rabeno B, Kwon SY, Penny R, Gardner J, Kemkes A, Mallery D, Morris S, Shelton T, Shelton C, Curley E, Alexopoulou I, Engel J, Bartlett J, Albert M, Park DY, Dhir R, Luketich J, Landreneau R, Janjigian YY, Kelsen DP, Cho E, Ladanyi M, Tang L, McCall SJ, Park YS, Cheong JH, Ajani J, Constanza Camargo M, Alonso S, Ayala B, Jensen MA, Pihl T, Raman R, Walton J, Wan Y, Demchok JA, Eley G, Mills Shaw KR, Sheth M, Tarnuzzer R, Wang Z, Yang L, Claude Zenklusen J, Davidsen T, Hutter CM, Sofia HJ, Burton R, Chudamani S, Liu J (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209

    Article  Google Scholar 

  17. 17.

    Wang K, Yuen ST, Xu J, Lee SP, Yan HHN, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan ASY, Tsui WY, Ho SL, Chan AKW, Man JLK, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GHW, Xie T, Fernandez J, Li VSW, Clevers H, Rejto PA, Mao M, Leung SY (2014) Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46:573–582

    CAS  Article  Google Scholar 

  18. 18.

    Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, Kelsen DP (2011) Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 17:2693–2701

    CAS  Article  Google Scholar 

  19. 19.

    Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S, Chua C, Feng Z, Guan YK, Ooi CH, Ivanova T, Zhang S, Lee M, Wu J, Ngo A, Manesh S, Tan E, Teh BT, So JBY, Goh LK, Boussioutas A, Lim TKH, Flotow H, Tan P, Rozen SG (2013) Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology 145:554–565

    CAS  Article  Google Scholar 

  20. 20.

    Birkman EM, Mansuri N, Kurki S, Âlgars A, Lintunen M, Ristamäki R et al (2018) Gastric cancer: immunohistochemical classification of molecular subtypes and their association with clinicopathological characteristics. Virchows Arch 472:369–382

    CAS  Article  Google Scholar 

  21. 21.

    Gonzalez RS, Messing S, Tu X, McMahon LA, Whitney-Miller CL (2016) Immunohistochemistry as a surrogate for molecular subtyping of gastric carcinoma. Hum Pathol 56:16–21

    CAS  Article  Google Scholar 

  22. 22.

    Kim DH, Shin N, Kim GH, Song GA, Jeon TY, Kim DH, Lauwers GY, Park DY (2013) Mucin expression in gastric cancer. Arch Pathol Lab Med 137:1047–1053

    Article  Google Scholar 

  23. 23.

    Lastraioli E, Romoli MR, Arcangeli A (2012) Immunohistochemical biomarkers in gastric cancer research and management. Int J Surg Oncol 2012:868645

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Badary DM, Abdel-Wanis ME, Hafez MZ, Aboulhagag NA (2017) Immunohistochemical analysis of PTEN, HER2/neu and ki67 expression in patients with gastric cancer and their association with survival. Pathophysiology 24:99–106

    CAS  Article  Google Scholar 

  25. 25.

    Guner G, Isik A, Karabulit E, Gedikoglu G, Sokmensuer C, Akyol A (2018) Morphologic and immunohistochemical appraisal of primary gastric carcinomas. Appl Immunohistochem Mol Morphol:1. https://doi.org/10.1097/PAI.0000000000000618

  26. 26.

    Li GQ, He Q, Yang L, Wang SB, Yu DD, He YQ, Hu J, Pan YM, Wu Y (2017) Clinical significance of myeloid zinc finger 1 expression in the progression of gastric tumorigenesis. Cell Physiol Biochem 44:1242–1250

    CAS  Article  Google Scholar 

  27. 27.

    Chia N-Y, Tan P (2016) Molecular classification of gastric cancer. Ann Oncol 27:763–769

    Article  Google Scholar 

  28. 28.

    Chen K, Yang D, Li X, Sun B, Song F, Cao W, Brat DJ, Gao Z, Li H, Liang H, Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce CM, Wang YM, Raghavakaimal S, Li H, Lu X, Pan Y, Chang H, Ba S, Luo L, Cavenee WK, Zhang W, Hao X (2015) Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. Proc Natl Acad Sci 112:1107–1112

    CAS  Article  Google Scholar 

  29. 29.

    Yao Y, Tao H, Kim JJ, Burkhead B, Carloni E, Gasbarrini A, Sepulveda AR (2004) Alterations of DNA mismatch repair proteins and microsatellite instability levels in gastric cancer cell lines. Lab Investig 84:915–922

    CAS  Article  Google Scholar 

  30. 30.

    Majewski IJ, Kluijt I, Cats A, Scerri TS, de Jong D, Kluin RJ et al (2013) An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol 229:621–629

    CAS  Article  Google Scholar 

  31. 31.

    Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, Yamamoto S, Tatsuno K, Katoh H, Watanabe Y, Ichimura T, Ushiku T, Funahashi S, Tateishi K, Wada I, Shimizu N, Nomura S, Koike K, Seto Y, Fukayama M, Aburatani H, Ishikawa S (2014) Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet 46:583–587

    CAS  Article  Google Scholar 

  32. 32.

    Cai J, Feng D, Hu L, Chen H, Yang G, Cai Q, Gao C, Wei D (2015) FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/β-catenin signalling. Br J Cancer 113:1720–1729

    CAS  Article  Google Scholar 

  33. 33.

    Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J et al (2012) Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 44:570–574

    CAS  Article  Google Scholar 

  34. 34.

    Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, Chan TL, Kan Z, Chan ASY, Tsui WY, Lee SP, Ho SL, Chan AKW, Cheng GHW, Roberts PC, Rejto PA, Gibson NW, Pocalyko DJ, Mao M, Xu J, Leung SY (2011) Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 43:1219–1223

    CAS  Article  Google Scholar 

  35. 35.

    Takeshima H, Niwa T, Takahashi T, Wakabayashi M, Yamashita S, Ando T, Inagawa Y, Taniguchi H, Katai H, Sugiyama T, Kiyono T, Ushijima T (2015) Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer Lett 357:328–338

    CAS  Article  Google Scholar 

  36. 36.

    Chen Z, Raghoonundun C, Chen W, Zhang Y, Tang W, Fan X, et al (2018) SETD2 indicates favourable prognosis in gastric cancer and suppresses cancer cell proliferation, migration, and invasion. Biochem Biophys Res Commun. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29522714

  37. 37.

    Noguchi A, Kikuchi K, Zheng H, Takahashi H, Miyagi Y, Aoki I, Takano Y (2014) SIRT1 expression is associated with a poor prognosis, whereas DBC1 is associated with favorable outcomes in gastric cancer. Cancer Med 3:1553–1561

    CAS  Article  Google Scholar 

  38. 38.

    Chiurillo MA (2015) Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review. World J Exp Med 5:84–102

    Article  Google Scholar 

  39. 39.

    Xu W-T, Yang Z, Lu N-H (2014) Roles of PTEN (Phosphatase and Tensin Homolog) in gastric cancer development and progression. Asian Pac J Cancer Prev 15:17–24

    CAS  Article  Google Scholar 

  40. 40.

    Willems L, Tamburini J, Chapuis N, Lacombe C, Mayeux P, Bouscary D (2012) PI3K and mTOR signaling pathways in cancer: new data on targeted therapies. Curr Oncol Rep 14:129–138

    CAS  Article  Google Scholar 

  41. 41.

    Chen D, Lin X, Zhang C, Liu Z, Chen Z, Li Z, Wang J, Li B, Hu Y, Dong B, Shen L, Ji J, Gao J, Zhang X (2018) Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway. Cell Death Dis 9:123

    Article  Google Scholar 

  42. 42.

    Becker JC, Muller-Tidow C, Serve H, Domschke W, Pohle T (2006) Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy. World J Gastroenterol 12:3297–3305

    CAS  Article  Google Scholar 

  43. 43.

    Park CK, Park JS, Kim HS, Rha SY, Hyung WJ, Cheong J-H et al (2016) Receptor tyrosine kinase amplified gastric cancer: clinicopathologic characteristics and proposed screening algorithm. Oncotarget 7:72099–72112

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee M, Wu J, Lim KH, Lei Z, Goh G, Lim QY, Tan ALK, Sin Poh DY, Riahi S, Bell S, Shi MM, Linnartz R, Zhu F, Yeoh KG, Toh HC, Yong WP, Cheong HC, Rha SY, Boussioutas A, Grabsch H, Rozen S, Tan P (2012) A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61:673–684

    CAS  Article  Google Scholar 

  45. 45.

    Gu L, Chen M, Guo D, Zhu H, Zhang W, Pan J, et al (2017) PD-L1 and gastric cancer prognosis: a systematic review and meta-analysis. Katoh M, editor. PLoS One 12:e0182692

  46. 46.

    Xing X, Guo J, Ding G, Li B, Dong B, Feng Q, Li S, Zhang J, Ying X, Cheng X, Guo T, du H, Hu Y, Zhou T, Wang X, Li L, Li Q, Xie M, Li L, Gao X, Shan F, Li Z, Jia S, Wen X, Wang J, Ji J (2018) Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology 7:e1356144

    Article  Google Scholar 

  47. 47.

    Ooi A, Oyama T, Nakamura R, Tajiri R, Ikeda H, Fushida S, Dobashi Y (2017) Gene amplification of CCNE1 , CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Hum Pathol 61:58–67

    CAS  Article  Google Scholar 

  48. 48.

    Stahl P, Seeschaaf C, Lebok P, Kutup A, Bockhorn M, Izbicki JR, Bokemeyer C, Simon R, Sauter G, Marx AH (2015) Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer. BMC Gastroenterol 15:7

    CAS  Article  Google Scholar 

  49. 49.

    Yang T, Chen M, Yang X, Zhang X, Zhang Z, Sun Y, Xu B, Hua J, He Z, Song Z (2017) Down-regulation of KLF5 in cancer-associated fibroblasts inhibit gastric cancer cells progression by CCL5/CCR5 axis. Cancer Biol Ther 18:806–815

    CAS  Article  Google Scholar 

  50. 50.

    Ma P, Sun C-Q, Wang Y-F, Pan Y-T, Chen Q-N, Liu W-T et al (2017) KLF16 promotes proliferation in gastric cancer cells via regulating p21 and CDK4. Am J Transl Res 9:3027–3036

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Chia N-Y, Deng N, Das K, Huang D, Hu L, Zhu Y, Lim KH, Lee MH, Wu J, Sam XX, Tan GS, Wan WK, Yu W, Gan A, Tan ALK, Tay ST, Soo KC, Wong WK, Dominguez LTM, Ng HH, Rozen S, Goh LK, Teh BT, Tan P (2015) Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut 64:707–719

    CAS  Article  Google Scholar 

  52. 52.

    Qu Y, Dang S, Hou P (2013) Gene methylation in gastric cancer. Clin Chim Acta 424:53–65

    CAS  Article  Google Scholar 

  53. 53.

    Graziano F, Humar B, Guilford P (2003) The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol Off J Eur Soc Med Oncol 14:1705–1713

    CAS  Article  Google Scholar 

  54. 54.

    Tahara T, Arisawa T (2015) DNA methylation as a molecular biomarker in gastric cancer. Epigenomics 7:475–486

    CAS  Article  Google Scholar 

  55. 55.

    Lin X, Zhao Y, Song W-M, Zhang B (2015) Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J 13:448–458

    CAS  Article  Google Scholar 

  56. 56.

    Wu Y, Grabsch H, Ivanova T, Tan IB, Murray J, Ooi CH, Wright AI, West NP, Hutchins GGA, Wu J, Lee M, Lee J, Koo JH, Yeoh KG, van Grieken N, Ylstra B, Rha SY, Ajani JA, Cheong JH, Noh SH, Lim KH, Boussioutas A, Lee JS, Tan P (2013) Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer. Gut 62:1100–1111

    CAS  Article  Google Scholar 

  57. 57.

    Zhang Y-Z, Zhang L-H, Gao Y, Li C-H, Jia S-Q, Liu N et al (2011) Discovery and validation of prognostic markers in gastric cancer by genome-wide expression profiling. World J Gastroenterol 17:1710–1717

    Article  Google Scholar 

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Correspondence to Cristina Díaz del Arco.

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Díaz del Arco, C., Estrada Muñoz, L., Molina Roldán, E. et al. Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival. Virchows Arch 473, 687–695 (2018). https://doi.org/10.1007/s00428-018-2443-9

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Keywords

  • Molecular
  • Gastric
  • Classification
  • Immunohistochemistry
  • Prognosis