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


METHODS
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.
Department of Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore.
Suling J
SJ
Lin
Department of Statistics, University of California at Berkeley, Berkeley, California, USA.
Johann A
JA
Gagnon-Bartsch
Department of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Iain Beehuat
IB
Tan
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Sophie
S
Earle
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Louise
L
Ruff
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Katherine
K
Pettinger
Department of Pathology, Free University Medical Center Amsterdam, Amsterdam, The Netherlands.
Bauke
B
Ylstra
Department of Pathology, Free University Medical Center Amsterdam, Amsterdam, The Netherlands.
Nicole
N
van Grieken
Department of Internal Medicine, Yonsei Cancer Center, Seoul, South Korea.
Sun Young
SY
Rha
Department of Internal Medicine, Yonsei Cancer Center, Seoul, South Korea.
Hyun Cheol
HC
Chung
Division of Cancer Medicine, Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA.
Ju-Seog
JS
Lee
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
Jae Ho
JH
Cheong
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
Sung Hoon
SH
Noh
Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan.
Toru
T
Aoyama
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
Yohei
Y
Miyagi
Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
Akira
A
Tsuburaya
Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan.
Takaki
T
Yoshikawa
Departments of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, USA.
Jaffer A
JA
Ajani
Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Department of Medicine Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
Alex
A
Boussioutas
Department of Medicine, National University Health System, Singapore, Singapore Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore.
Khay Guan
KG
Yeoh
National University Cancer Institute, Singapore, Singapore.
Wei Peng
WP
Yong
Department of Surgery, National University Health System, Singapore, Singapore.
Jimmy
J
So
Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Jeeyun
J
Lee
Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Won Ki
WK
Kang
Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Sung
S
Kim
Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, Japan.
Yoichi
Y
Kameda
Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
Tomio
T
Arai
Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
Axel
A
Zur Hausen
Department of Statistics, University of California at Berkeley, Berkeley, California, USA Bioinformatics Division, Walter and Eliza Hall Institute, Victoria, Australia Department of Mathematics and Statistics, University of Melbourne, Australia.
Terence P
TP
Speed
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
Heike I
HI
Grabsch
Department of Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore.
Patrick
P
Tan
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult
GASTRIC CANCER; GENE EXPRESSION; IMMUNOLOGY; MOLECULAR MECHANISMS; MOLECULAR PATHOLOGY