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Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10
Bridget Charbonneau1, Matthew S Block, William R Bamlet
1Authors' Affiliations: Departments of Health Sciences Research, Division of Epidemiology, Medical Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Immunology, and Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota; Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida; Channing Division of Network Medicine, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut; Department of Clinical Science, University of Bergen; Departments of Gynecology and Obstetrics, and Pathology, Haukeland University Hospital, Bergen, Norway; Departments for Health Evidence, Urology, and Gynaecology, Radboud University Medical Centre, Nijmegen; Comprehensive Cancer Center The Netherlands, Utrecht, the Netherlands; Cancer Epidemiology Centre, The Cancer Council Victoria; Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, Department of Pathology, and Sir Peter MacCallum Department of Oncology, University of Melbourne; Department of Epidemiology and Preventive Medicine, Monash University; Peter MacCallum Cancer Institute; Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria; Cancer Division, Queensland Institute of Medical Research, Herston, Queensland, Australia; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Department of Health Research and Policy, Division of Epidemiology, Stanford University School of Medicine, Palo Alto; Samuel Oschin Comprehensive Cancer Institute; Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; Department of Preventive Medicine, Keck School of Medicine, University of Sout
Abstract:
A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.
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