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Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives

Runnebaum, Ingo B.a,b; Wang-Gohrke, Shana; Vesprini, Dannyc; Kreienberg, Rolfa; Lynch, Henryd; Moslehi, Roxanac; Ghadirian, Parvize; Weber, Barbaraf; Godwin, Andrew K.g; Risch, Harveyh; Garber, Judyi; Lerman, Carynj; Olopade, Olufunmilayo I.k; Foulkes, William D.l; Karlan, Bethm; Warner, Ellenn; Rosen, Barryo; Rebbeck, Timothyf; Tonin, Patriciak; Dubé, Marie-Pierrec; Kieback, Dirk G.b; Narod, Steven A.c

Pharmacogenetics:
Original Article
Abstract

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5–1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4–4.3). The association was present after adjustment for ethnic group and for year of birth.

Author Information

aDepartment of Obstetrics and Gynecology, University of Ulm, Ulm, Germany, bDepartment of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany, cThe Center for Research in Women's Health, University of Toronto, Toronto, Canada, dCreighton University, Omaha, NE, USA, eCentre Hospitalier Université de Montreal, Canada, fDepartments of Medicine, Genetics, Biostatistics and Cancer Center, University of Pennsylvania, Philadelphia, PA, USA, gDivisions of Medical Sciences, Fox Chase Cancer Center, Philadelphia, PA, USA, hDepartment of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA, iDana Farber Cancer Institute, Boston, MA, USA, jLombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA, kSection of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA, lDepartments of Medicine, Human Genetics and Oncology, McGill University, Montreal, Canada, mCedars-Sinai Hospital, Los Angeles, CA, USA, nToronto-Sunnybrook Regional Cancer Center, Toronto, Canada and oDepartment of Obstetrics and Gynecology, The Toronto Hospital, Toronto, Canada

Received 27 April 2000; accepted 8 March 2001

Correspondence to Steven Narod, The Center for Research in Women's Health, 790 Bay Street, Toronto, M5G 1N8, Canada Tel: +416 351 3765; fax: +416 351 3767; e-mail: steven.narod@swchsc.on.ca

© 2001 Lippincott Williams & Wilkins, Inc.