Article Text

Original article
Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas
  1. Suling J Lin1,
  2. Johann A Gagnon-Bartsch2,
  3. Iain Beehuat Tan3,
  4. Sophie Earle4,
  5. Louise Ruff4,
  6. Katherine Pettinger4,
  7. Bauke Ylstra5,
  8. Nicole van Grieken5,
  9. Sun Young Rha6,
  10. Hyun Cheol Chung6,
  11. Ju-Seog Lee7,
  12. Jae Ho Cheong8,
  13. Sung Hoon Noh8,
  14. Toru Aoyama9,
  15. Yohei Miyagi10,
  16. Akira Tsuburaya11,
  17. Takaki Yoshikawa9,
  18. Jaffer A Ajani12,
  19. Alex Boussioutas13,14,
  20. Khay Guan Yeoh15,16,
  21. Wei Peng Yong17,
  22. Jimmy So18,
  23. Jeeyun Lee19,
  24. Won Ki Kang19,
  25. Sung Kim20,
  26. Yoichi Kameda21,
  27. Tomio Arai22,
  28. Axel zur Hausen23,24,
  29. Terence P Speed2,25,26,
  30. Heike I Grabsch4,23,24,
  31. Patrick Tan1,27,28,29
  1. 1Department of Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore
  2. 2Department of Statistics, University of California at Berkeley, Berkeley, California, USA
  3. 3Department of Medical Oncology, National Cancer Centre, Singapore, Singapore
  4. 4Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
  5. 5Department of Pathology, Free University Medical Center Amsterdam, Amsterdam, The Netherlands
  6. 6Department of Internal Medicine, Yonsei Cancer Center, Seoul, South Korea
  7. 7Division of Cancer Medicine, Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA
  8. 8Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
  9. 9Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan
  10. 10Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
  11. 11Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
  12. 12Departments of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, USA
  13. 13Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  14. 14Department of Medicine Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  15. 15Department of Medicine, National University Health System, Singapore, Singapore
  16. 16Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
  17. 17National University Cancer Institute, Singapore, Singapore
  18. 18Department of Surgery, National University Health System, Singapore, Singapore
  19. 19Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea
  20. 20Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
  21. 21Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan
  22. 22Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
  23. 23Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
  24. 24GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
  25. 25Bioinformatics Division, Walter and Eliza Hall Institute, Victoria, Australia
  26. 26Department of Mathematics and Statistics, University of Melbourne, Australia
  27. 27Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore
  28. 28Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
  29. 29Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore
  1. Correspondence to Dr Patrick Tan, Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore 169610, Singapore; gmstanp{at}duke-nus.edu.sg Dr Heike I Grabsch, Maastricht University Medical Center, Department of Pathology, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands; Heike.Grabsch@mumc.nl

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.

  • GASTRIC CANCER
  • GENE EXPRESSION
  • MOLECULAR PATHOLOGY
  • IMMUNOLOGY
  • MOLECULAR MECHANISMS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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