Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Huntsman Cancer Institute, Salt Lake City, UT, USA.
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
- Biomedical Informatics Program, Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
- Division of Biostatistics, Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
- University of Hawaii Cancer Center, Honolulu, HI, USA.
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
- Department of Global Health, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
- Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL,Canada.
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Population Science, American Cancer Society, Atlanta, GA, USA.
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
- Department of Genetics, Stanford University, Stanford, CA, USA.
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.
METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.
RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4).
CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS)