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

Oral contraceptives have been shown to be protective against hereditary ova rian cancer. The variant progesterone receptor allele named PROGINS is char acterized 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 i ncreased 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 mutati on and 183 women had a BRCA2 mutation. Overall, there was no association be tween 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 contracep tive use (74 cases and 365 controls), no modifying effect of PROGINS was ob served [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among t he 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 allel e (P = 0.004; 95% Cl 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth. Pharmacogenetics 11:635-638 (C) 20 01 Lippincott Williams & Wilkins.