title: Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.
abstract: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women.
  
  
  
  We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.
  
  
  
  SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)).
  
  
  
  We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions.
  
  
  
  Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas.
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authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas.
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authors.affiliation: Department of Oncology, University of Cambridge Strangeways Research Laboratory, Cambridge, United Kingdom.
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authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California.
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authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California.
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, California.
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authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
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authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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authors.affiliation: Discipline of Obstetrics, Gynecology, and Neonatology, University of Sydney, Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
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authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
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authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
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authors.affiliation: Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
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authors.affiliation: Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
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authors.affiliation: Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
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authors.lastname: Lurie
authors.affiliation: Department of Obstetrics & Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands.
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authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Usha
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authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California.
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authors.affiliation: Department of Oncology, University of Cambridge Strangeways Research Laboratory, Cambridge, United Kingdom.
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authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
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authors.affiliation: Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
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authors.affiliation: Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
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authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California.
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authors.initials: CL
authors.lastname: Pearce
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
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authors.affiliation: Department of Oncology, University of Cambridge Strangeways Research Laboratory, Cambridge, United Kingdom. Department of Public Health and Primary Care, University of Cambridge Strangeways Research Laboratory, Cambridge, United Kingdom.
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authors.lastname: Pharoah
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authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas. bfridley@kumc.edu.
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mesh_terms: D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008875:Middle Aged; D009765:Obesity; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors