Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival
- 548 Downloads
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.
KeywordsMolecular Gastric Classification Immunohistochemistry Prognosis
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
For this type of study formal consent is not required. This study has been reviewed and approved by the Ethics Committee at Hospital Clínico San Carlos.
- 4.Bosman F, Carneiro F, Hruban RH (2010) WHO classification of tumors of the digestive system, 4th edn. IARC, LyonGoogle Scholar
- 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 21:449–456CrossRefGoogle Scholar
- 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 24:1248–1253CrossRefGoogle Scholar
- 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 513:202–209CrossRefGoogle Scholar
- 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 46:573–582CrossRefGoogle Scholar
- 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 145:554–565CrossRefGoogle Scholar
- 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
- 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 112:1107–1112CrossRefGoogle Scholar
- 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 46:583–587CrossRefGoogle Scholar
- 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 43:1219–1223CrossRefGoogle Scholar
- 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
- 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 9:123CrossRefGoogle Scholar
- 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 61:673–684CrossRefGoogle Scholar
- 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:e0182692Google Scholar
- 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:e1356144CrossRefGoogle Scholar
- 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 64:707–719CrossRefGoogle Scholar
- 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 62:1100–1111CrossRefGoogle Scholar