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

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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.

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Most cited references 30

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Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

Kerby Shedden, Jeremy M. G. Taylor, Steven A. Enkemann … (2008)

Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

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Epidemiology of gastric cancer.

Katherine D Crew, Alfred I Neugut (2006)

The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socio-economic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socio-economic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori (H pylori) infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.

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Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells.

Farbod Shojaei, Xiumin Wu, Ajay K. Malik … (2007)

Vascular endothelial growth factor (VEGF) is an essential regulator of normal and abnormal blood vessel growth. A monoclonal antibody (mAb) that targets VEGF suppresses tumor growth in murine cancer models and human patients. We investigated cellular and molecular events that mediate refractoriness of tumors to anti-angiogenic therapy. Inherent anti-VEGF refractoriness is associated with infiltration of the tumor tissue by CD11b+Gr1+ myeloid cells. Recruitment of these myeloid cells is also sufficient to confer refractoriness. Combining anti-VEGF treatment with a mAb that targets myeloid cells inhibits growth of refractory tumors more effectively than anti-VEGF alone. Gene expression analysis in CD11b+Gr1+ cells isolated from the bone marrow of mice bearing refractory tumors reveals higher expression of a distinct set of genes known to be implicated in active mobilization and recruitment of myeloid cells. These findings indicate that, in our models, refractoriness to anti-VEGF treatment is determined by the ability of tumors to prime and recruit CD11b+Gr1+ cells.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): November 2015

Publication date (Electronic): 10 November 2014

Volume: 64

Issue: 11

Pages: 1721-1731

Affiliations

[1 ]Department of Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore , Singapore, Singapore

[2 ]Department of Statistics, University of California at Berkeley , Berkeley, California, USA

[3 ]Department of Medical Oncology, National Cancer Centre , Singapore, Singapore

[4 ]Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds , Leeds, UK

[5 ]Department of Pathology, Free University Medical Center Amsterdam , Amsterdam, The Netherlands

[6 ]Department of Internal Medicine, Yonsei Cancer Center , Seoul, South Korea

[7 ]Division of Cancer Medicine, Department of Systems Biology, MD Anderson Cancer Center , Houston, Texas, USA

[8 ]Department of Surgery, Yonsei University College of Medicine , Seoul, South Korea

[9 ]Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital , Yokohama, Japan

[10 ]Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute , Yokohama, Japan

[11 ]Gastroenterological Center, Yokohama City University Medical Center , Yokohama, Japan

[12 ]Departments of Gastrointestinal Medical Oncology, MD Anderson Cancer Center , Houston, USA

[13 ]Cancer Genomics and Biochemistry Laboratory, Peter MacCallum Cancer Centre , East Melbourne, Victoria, Australia

[14 ]Department of Medicine Royal Melbourne Hospital, University of Melbourne , Parkville, Victoria, Australia

[15 ]Department of Medicine, National University Health System , Singapore, Singapore

[16 ]Department of Gastroenterology and Hepatology, National University Health System , Singapore, Singapore

[17 ]National University Cancer Institute , Singapore, Singapore

[18 ]Department of Surgery, National University Health System , Singapore, Singapore

[19 ]Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine , Seoul, South Korea

[20 ]Department of Surgery, Gastric Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, South Korea

[21 ]Department of Pathology, Kanagawa Cancer Center Hospital , Yokohama, Japan

[22 ]Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology , Tokyo, Japan

[23 ]Department of Pathology, Maastricht University Medical Center , Maastricht, The Netherlands

[24 ]GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands

[25 ]Bioinformatics Division, Walter and Eliza Hall Institute , Victoria, Australia

[26 ]Department of Mathematics and Statistics, University of Melbourne , Australia

[27 ]Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School , Singapore, Singapore

[28 ]Cancer Science Institute of Singapore, National University of Singapore , Singapore, Singapore

[29 ]Cellular and Molecular Research, National Cancer Centre , Singapore, Singapore

Author notes

[Correspondence to ] Dr Patrick Tan, Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore 169610, Singapore; gmstanp@ 123456duke-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

Article

Publisher ID: gutjnl-2014-308252

DOI: 10.1136/gutjnl-2014-308252

PMC ID: 4680172

PubMed ID: 25385008

SO-VID: a44c753c-3235-4122-a0b9-45d35c4963f5

License:

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/

History

Date received : 13 August 2014

Date revision received : 8 September 2014

Date accepted : 9 September 2014

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: gastric cancer,gene expression,molecular pathology,immunology,molecular mechanisms

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: gastric cancer, gene expression, molecular pathology, immunology, molecular mechanisms

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

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Karger: Gastroenterology

Most cited references 30

Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

Epidemiology of gastric cancer.

Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells.

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