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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Research Articles

Genetic Variants in the Regulatory T cell–Related Pathway and Colorectal Cancer Prognosis

Sonja Neumeyer, Xinwei Hua, Petra Seibold, Lina Jansen, Axel Benner, Barbara Burwinkel, Niels Halama, Sonja I. Berndt, Amanda I. Phipps, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Andrew T. Chan, Manish Gala, Amit D. Joshi, Shuji Ogino, Mingyang Song, Esther Herpel, Hendrik Bläker, Matthias Kloor, Dominique Scherer, Alexis Ulrich, Cornelia M. Ulrich, Aung K. Win, Jane C. Figueiredo, John L. Hopper, Finlay Macrae, Roger L. Milne, Graham G. Giles, Daniel D. Buchanan, Ulrike Peters, Michael Hoffmeister, Hermann Brenner, Polly A. Newcomb and Jenny Chang-Claude
Sonja Neumeyer
1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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Xinwei Hua
3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
4School of Public Health, University of Washington, Seattle, Washington.
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  • ORCID record for Xinwei Hua
Petra Seibold
1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Lina Jansen
5Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.
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  • ORCID record for Lina Jansen
Axel Benner
6Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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  • ORCID record for Axel Benner
Barbara Burwinkel
7Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8Department of Gynecology and Obstetrics, Molecular Biology of Breast Cancer, University of Heidelberg, Heidelberg, Germany.
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Niels Halama
9Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
10Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, Heidelberg, Germany.
11Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany.
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Sonja I. Berndt
12Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
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Amanda I. Phipps
3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
13Epidemiology Department, University of Washington, Seattle, Washington.
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Lori C. Sakoda
3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
14Division of Research, Kaiser Permanente Northern California, Oakland, California.
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Robert E. Schoen
15Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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  • ORCID record for Robert E. Schoen
Martha L. Slattery
16Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
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Andrew T. Chan
17Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
18Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
19Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Manish Gala
17Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
19Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Amit D. Joshi
19Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
20Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
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Shuji Ogino
20Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
21Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
22Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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Mingyang Song
17Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
19Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
20Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
23Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
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Esther Herpel
24NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
25Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
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Hendrik Bläker
26Institute of Pathology, Charité University Medicine, Berlin, Germany.
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Matthias Kloor
27Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
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Dominique Scherer
28Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany.
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  • ORCID record for Dominique Scherer
Alexis Ulrich
29Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Germany.
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Cornelia M. Ulrich
30Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah.
31Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
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  • ORCID record for Cornelia M. Ulrich
Aung K. Win
32Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia.
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Jane C. Figueiredo
33Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles California.
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John L. Hopper
34Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia.
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Finlay Macrae
34Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia.
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Roger L. Milne
32Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia.
35Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
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Graham G. Giles
32Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia.
35Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
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Daniel D. Buchanan
36Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
37University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
38Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
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Ulrike Peters
3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
39Department of Epidemiology, University of Washington, Seattle, Washington.
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Michael Hoffmeister
5Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.
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Hermann Brenner
5Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.
40Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
41German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Polly A. Newcomb
2Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Jenny Chang-Claude
1Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
42Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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  • For correspondence: j.chang-claude@dkfz-heidelberg.de
DOI: 10.1158/1055-9965.EPI-20-0714 Published December 2020
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Abstract

Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis.

Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer–specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC).

Results: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer–specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74–0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68–0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed.

Conclusions: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients.

Impact: The implicated genes warrant further investigation.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

  • Cancer Epidemiol Biomarkers Prev 2020;29:2719–28

  • Received May 11, 2020.
  • Revision received July 29, 2020.
  • Accepted September 28, 2020.
  • Published first October 2, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Epidemiology Biomarkers & Prevention: 29 (12)
December 2020
Volume 29, Issue 12
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Genetic Variants in the Regulatory T cell–Related Pathway and Colorectal Cancer Prognosis
Sonja Neumeyer, Xinwei Hua, Petra Seibold, Lina Jansen, Axel Benner, Barbara Burwinkel, Niels Halama, Sonja I. Berndt, Amanda I. Phipps, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Andrew T. Chan, Manish Gala, Amit D. Joshi, Shuji Ogino, Mingyang Song, Esther Herpel, Hendrik Bläker, Matthias Kloor, Dominique Scherer, Alexis Ulrich, Cornelia M. Ulrich, Aung K. Win, Jane C. Figueiredo, John L. Hopper, Finlay Macrae, Roger L. Milne, Graham G. Giles, Daniel D. Buchanan, Ulrike Peters, Michael Hoffmeister, Hermann Brenner, Polly A. Newcomb and Jenny Chang-Claude
Cancer Epidemiol Biomarkers Prev December 1 2020 (29) (12) 2719-2728; DOI: 10.1158/1055-9965.EPI-20-0714

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Genetic Variants in the Regulatory T cell–Related Pathway and Colorectal Cancer Prognosis
Sonja Neumeyer, Xinwei Hua, Petra Seibold, Lina Jansen, Axel Benner, Barbara Burwinkel, Niels Halama, Sonja I. Berndt, Amanda I. Phipps, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Andrew T. Chan, Manish Gala, Amit D. Joshi, Shuji Ogino, Mingyang Song, Esther Herpel, Hendrik Bläker, Matthias Kloor, Dominique Scherer, Alexis Ulrich, Cornelia M. Ulrich, Aung K. Win, Jane C. Figueiredo, John L. Hopper, Finlay Macrae, Roger L. Milne, Graham G. Giles, Daniel D. Buchanan, Ulrike Peters, Michael Hoffmeister, Hermann Brenner, Polly A. Newcomb and Jenny Chang-Claude
Cancer Epidemiol Biomarkers Prev December 1 2020 (29) (12) 2719-2728; DOI: 10.1158/1055-9965.EPI-20-0714
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