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

102 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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    Lin, S. J., Gagnon-Bartsch, J. A., Tan, I. B., Earle, S., Ruff, L., Pettinger, K., Ylstra, B., Van Grieken, N., Rha, S. Y., Chung, H. C., Lee, J. S., Cheong, J. H., Noh, S. H., Aoyama, T., Miyagi, Y., Tsuburaya, A., Yoshikawa, T., Ajani, J. A., Boussioutas, A., ... 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