Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction

被引：18

作者：

Bornschein, Jan ^{[1
,2
,3
]}

Wernisch, Lorenz ^{[4
]}

Secrier, Maria ^{[5
]}

Miremadi, Ahmad ^{[6
]}

Perner, Juliane ^{[5
]}

MacRae, Shona ^{[1
]}

O'Donovan, Maria ^{[6
]}

Newton, Richard ^{[4
]}

Menon, Suraj ^{[5
]}

Bower, Lawrence ^{[5
]}

Eldridge, Matthew D. ^{[5
]}

Devonshire, Ginny ^{[5
]}

Cheah, Calvin ^{[1
]}

Turkington, Richard ^{[7
]}

Hardwick, Richard H. ^{[8
]}

Selgrad, Michael ^{[2
]}

Venerito, Marino ^{[2
]}

Malfertheiner, Peter ^{[2
]}

Fitzgerald, Rebecca C. ^{[1
]}

Noorani, Ayesha ^{[1
]}

Elliott, Rachael Fels ^{[1
]}

Edwards, Paul A. W. ^{[1
,5
]}

Grehan, Nicola ^{[1
]}

Nutzinger, Barbara ^{[1
]}

Crawte, Jason ^{[1
]}

Chettouh, Hamza ^{[1
]}

Contino, Gianmarco ^{[1
]}

Li, Xiaodun ^{[1
]}

Gregson, Eleanor ^{[1
]}

Zeki, Sebastian ^{[1
]}

de la Rue, Rachel ^{[1
]}

Malhotra, Shalini ^{[1
,9
]}

Tavare, Simon ^{[5
]}

Lynch, Andy G. ^{[5
]}

Smith, Mike L. ^{[5
]}

Davies, Jim ^{[10
]}

Crichton, Charles ^{[10
]}

Carroll, Nick ^{[11
]}

Safranek, Peter ^{[11
]}

Hindmarsh, Andrew ^{[11
]}

Sujendran, Vijayendran ^{[11
]}

Hayes, Stephen J. ^{[12
,19
]}

Ang, Yeng ^{[12
,13
,34
]}

Preston, Shaun R. ^{[14
]}

Oakes, Sarah ^{[14
]}

Bagwan, Izhar ^{[14
]}

Save, Vicki ^{[15
]}

Skipworth, Richard J. E. ^{[15
]}

Hupp, Ted R. ^{[15
]}

O'Neill, J. Robert ^{[15
,28
]}

机构：

[1] Univ Cambridge, MRC, Hutchison MRC Res Ctr, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England

[2] Otto von Guericke Univ, Dept Gastroenterol Hepatol & Infect Dis, Magdeburg, Germany

[3] Oxford Univ Hosp, Translat Gastroenterol Unit, Oxford, England

[4] Univ Cambridge, Biostat Unit, MRC, Cambridge, England

[5] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[6] Cambridge Univ Hosp, Addenbrookes Hosp, Dept Histopathol, Cambridge, England

[7] Queens Univ, Dept Oncol, Belfast, Antrim, North Ireland

[8] Cambridge Univ Hosp, Addenbrookes Hosp, Dept Surg, Cambridge, England

[9] Addenbrookes Hosp, Dept Histopathol, Cambridge, England

[10] Univ Oxford, Dept Comp Sci, Oxford OX1 3QD, England

[11] Cambridge Univ Hosp NHS Fdn Trust, Cambridge CB2 0QQ, England

[12] Salford Royal NHS Fdn Trust, Salford M6 8HD, Lancs, England

[13] Wigan & Leigh NHS Fdn Trust, Manchester WN1 2NN, Lancs, England

[14] Royal Surrey Cty Hosp NHS Fdn Trust, Guildford GU2 7XX, Surrey, England

[15] Edinburgh Royal Infirm, Edinburgh EH16 4SA, Midlothian, Scotland

[16] Univ Hosp Birmingham NHS Fdn Trust, Birmingham B15 2GW, W Midlands, England

[17] Univ Hosp Southampton NHS Fdn Trust, Southampton SO16 6YD, Hants, England

[18] Univ Southampton, Canc Sci Div, Southampton SO17 1BJ, Hants, England

[19] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PL, Lancs, England

[20] Gloucester Royal Hosp, Gloucester GL1 3NN, England

[21] St Thomas Hosp, London SE1 7EH, England

[22] Plymouth Hosp NHS Trust, Plymouth PL6 8DH, Devon, England

[23] Norfolk & Norwich Univ Hosp NHS Fdn Trust, Norwich NR4 7UY, Norfolk, England

[24] Nottingham Univ Hosp NHS Trust, Nottingham NG7 2UH, England

[25] UCL, London WC1E 6BT, England

[26] Norfolk & Waveney Cellular Pathol Network, Norwich NR4 7UY, Norfolk, England

[27] Wythenshawe Hosp, Manchester M23 9LT, Lancs, England

[28] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland

[29] Kings Coll London, London, England

[30] Karolinska Inst, SE-17177 Stockholm, Sweden

[31] Univ Hosp Coventry andWarwickshire NHS Trust, Coventry CV2 2DX, W Midlands, England

[32] Peterborough Hosp NHS Trust, Peterborough City Hosp, Peterborough PE3 9GZ, Cambs, England

[33] Univ Birmingham, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands, England

[34] Univ Manchester, GI Sci Ctr, Manchester M13 9PL, Lancs, England

[35] Imperial Coll London, Imperial Coll NHS Trust, London W2 1NY, England

[36] Univ Nottingham, Queens Med Ctr, Nottingham, England

[37] Heart England NHS Fdn Trust, Birmingham B9 5SS, W Midlands, England

来源：

INTERNATIONAL JOURNAL OF CANCER | 2019年 / 145卷 / 12期

基金：

英国生物技术与生命科学研究理事会; 欧洲研究理事会; 英国医学研究理事会; 瑞士国家科学基金会;

关键词：

gastric cancer; esophageal adenocarcinoma; gastroesophageal junction; gene expression profiling; Siewert classification; GASTRIC-CANCER; BILE-ACIDS; EXPRESSION; ESOPHAGUS; SIGNATURE; PATHWAYS; SUBTYPES; CLASSIFICATION; IDENTIFICATION; PROGNOSIS;

D O I：

10.1002/ijc.32384

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment-naive, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune-response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed.

引用

页码：3389 / 3401

页数：13

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