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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.
Pubmed ID
35512400 (View this publication on the PubMed website)
Digital Object Identifier
J Natl Cancer Inst. 2022 Aug 8; Volume 114 (Issue 8): Pages 1135-1148
Tian Y , Kim AE , Bien SA , Lin Y , Qu C , Harrison TA , Carreras-Torres R , Díez-Obrero V , Dimou N , Drew DA , Hidaka A , Huyghe JR , Jordahl KM , Morrison J , Murphy N , Obón-Santacana M , Ulrich CM , Ose J , Peoples AR , Ruiz-Narvaez EA , more Shcherbina A , Stern MC , Su YR , van Duijnhoven FJB , Arndt V , Baurley JW , Berndt SI , Bishop DT , Brenner H , Buchanan DD , Chan AT , Figueiredo JC , Gallinger S , Gruber SB , Harlid S , Hoffmeister M , Jenkins MA , Joshi AD , Keku TO , Larsson SC , Le Marchand L , Li L , Giles GG , Milne RL , Nan H , Nassir R , Ogino S , Budiarto A , Platz EA , Potter JD , Prentice RL , Rennert G , Sakoda LC , Schoen RE , Slattery ML , Thibodeau SN , Van Guelpen B , Visvanathan K , White E , Wolk A , Woods MO , Wu AH , Campbell PT , Casey G , Conti DV , Gunter MJ , Kundaje A , Lewinger JP , Moreno V , Newcomb PA , Pardamean B , Thomas DC , Tsilidis KK , Peters U , Gauderman WJ , Hsu L , Chang-Claude J
  • 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. more
  • 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.

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