Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas

Suling J. Lin, Johann A. Gagnon-Bartsch, Iain Beehuat Tan, Sophie Earle, Louise Ruff, Katherine Pettinger, Bauke Ylstra, Nicole Van Grieken, Sun Young Rha, Hyun Cheol Chung, Ju Seog Lee, Jae Ho Cheong, Sung Hoon Noh, Toru Aoyama, Yohei Miyagi, Akira Tsuburaya, Takaki Yoshikawa, Jaffer A. Ajani, Alex Boussioutas, Khay Guan YeohWei Peng Yong, Jimmy So, Jeeyun Lee, Won Ki Kang, Sung Kim, Yoichi Kameda, Tomio Arai, Axel Zur Hausen, Terence P. Speed, Heike I. Grabsch, Patrick Tan

Research output: Contribution to journalArticle

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Abstract

Objective: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Conclusions: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

Original languageEnglish
Pages (from-to)1721-1731
Number of pages11
JournalGut
Volume64
Issue number11
DOIs
Publication statusPublished - 2015 Nov

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Stomach Neoplasms
Immunity
Stomach
Adenocarcinoma
T-Lymphocytes
Neoplasms
Geography
Regulatory T-Lymphocytes
Immunosuppressive Agents
Transcriptome
Cell Biology
Meta-Analysis
Inflammation
Gene Expression
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Lin, S. J., Gagnon-Bartsch, J. A., Tan, I. B., Earle, S., Ruff, L., Pettinger, K., ... Tan, P. (2015). Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut, 64(11), 1721-1731. https://doi.org/10.1136/gutjnl-2014-308252
Lin, Suling J. ; Gagnon-Bartsch, Johann A. ; Tan, Iain Beehuat ; Earle, Sophie ; Ruff, Louise ; Pettinger, Katherine ; Ylstra, Bauke ; Van Grieken, Nicole ; Rha, Sun Young ; Chung, Hyun Cheol ; Lee, Ju Seog ; Cheong, Jae Ho ; Noh, Sung Hoon ; Aoyama, Toru ; Miyagi, Yohei ; Tsuburaya, Akira ; Yoshikawa, Takaki ; Ajani, Jaffer A. ; Boussioutas, Alex ; Yeoh, Khay Guan ; Yong, Wei Peng ; So, Jimmy ; Lee, Jeeyun ; Kang, Won Ki ; Kim, Sung ; Kameda, Yoichi ; Arai, Tomio ; Zur Hausen, Axel ; Speed, Terence P. ; Grabsch, Heike I. ; Tan, Patrick. / Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. In: Gut. 2015 ; Vol. 64, No. 11. pp. 1721-1731.
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abstract = "Objective: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Conclusions: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.",
author = "Lin, {Suling J.} and Gagnon-Bartsch, {Johann A.} and Tan, {Iain Beehuat} and Sophie Earle and Louise Ruff and Katherine Pettinger and Bauke Ylstra and {Van Grieken}, Nicole and Rha, {Sun Young} and Chung, {Hyun Cheol} and Lee, {Ju Seog} and Cheong, {Jae Ho} and Noh, {Sung Hoon} and Toru Aoyama and Yohei Miyagi and Akira Tsuburaya and Takaki Yoshikawa and Ajani, {Jaffer A.} and Alex Boussioutas and Yeoh, {Khay Guan} and Yong, {Wei Peng} and Jimmy So and Jeeyun Lee and Kang, {Won Ki} and Sung Kim and Yoichi Kameda and Tomio Arai and {Zur Hausen}, Axel and Speed, {Terence P.} and Grabsch, {Heike I.} and Patrick Tan",
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Lin, SJ, Gagnon-Bartsch, JA, Tan, IB, Earle, S, Ruff, L, Pettinger, K, Ylstra, B, Van Grieken, N, Rha, SY, Chung, HC, Lee, JS, Cheong, JH, Noh, SH, Aoyama, T, Miyagi, Y, Tsuburaya, A, Yoshikawa, T, Ajani, JA, Boussioutas, A, Yeoh, KG, Yong, WP, So, J, Lee, J, Kang, WK, Kim, S, Kameda, Y, Arai, T, Zur Hausen, A, Speed, TP, Grabsch, HI & Tan, P 2015, 'Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas', Gut, vol. 64, no. 11, pp. 1721-1731. https://doi.org/10.1136/gutjnl-2014-308252

Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. / Lin, Suling J.; Gagnon-Bartsch, Johann A.; Tan, Iain Beehuat; Earle, Sophie; Ruff, Louise; Pettinger, Katherine; Ylstra, Bauke; Van Grieken, Nicole; Rha, Sun Young; Chung, Hyun Cheol; Lee, Ju Seog; Cheong, Jae Ho; Noh, Sung Hoon; Aoyama, Toru; Miyagi, Yohei; Tsuburaya, Akira; Yoshikawa, Takaki; Ajani, Jaffer A.; Boussioutas, Alex; Yeoh, Khay Guan; Yong, Wei Peng; So, Jimmy; Lee, Jeeyun; Kang, Won Ki; Kim, Sung; Kameda, Yoichi; Arai, Tomio; Zur Hausen, Axel; Speed, Terence P.; Grabsch, Heike I.; Tan, Patrick.

In: Gut, Vol. 64, No. 11, 11.2015, p. 1721-1731.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas

AU - Lin, Suling J.

AU - Gagnon-Bartsch, Johann A.

AU - Tan, Iain Beehuat

AU - Earle, Sophie

AU - Ruff, Louise

AU - Pettinger, Katherine

AU - Ylstra, Bauke

AU - Van Grieken, Nicole

AU - Rha, Sun Young

AU - Chung, Hyun Cheol

AU - Lee, Ju Seog

AU - Cheong, Jae Ho

AU - Noh, Sung Hoon

AU - Aoyama, Toru

AU - Miyagi, Yohei

AU - Tsuburaya, Akira

AU - Yoshikawa, Takaki

AU - Ajani, Jaffer A.

AU - Boussioutas, Alex

AU - Yeoh, Khay Guan

AU - Yong, Wei Peng

AU - So, Jimmy

AU - Lee, Jeeyun

AU - Kang, Won Ki

AU - Kim, Sung

AU - Kameda, Yoichi

AU - Arai, Tomio

AU - Zur Hausen, Axel

AU - Speed, Terence P.

AU - Grabsch, Heike I.

AU - Tan, Patrick

PY - 2015/11

Y1 - 2015/11

N2 - Objective: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Conclusions: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

AB - Objective: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. Design: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Results: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Conclusions: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

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Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut. 2015 Nov;64(11):1721-1731. https://doi.org/10.1136/gutjnl-2014-308252