Impact of Two Functional Progesterone Receptor Polymorphisms (PRP): +331G/A and PROGINS on the Cancer Risks in Familial Breast/Ovarian Cancer

Background: More than half of the families with breast and/or ovarian cancer (BC/OC) have no BRCA1 or BRCA2 mutation, moreover the broad lifetime risks reported within families with a BRCA1/2 mutation suggest other genes are also responsible. Objective: Assess the prevalence, gene-gene and phenotype-genotype associations of two functional progesterone receptor polymorphisms (PRP), PROGINS and +331G/A, in familial BC/OC. Methods: DNA samples from 318 randomly selected probands tested for BRCA1/2 mutations were genotyped for the PRP and CHEK2*1100delC variant. Results: BRCA1 was associated with BC at young age, p=0.002; +331A marginally with OC, p=0.07, and PROGINS with male BC, p=0.04. Homozygous +331A/A co-segregated with BRCA2 variants more frequently than expected by chance alone. Co-occurrence of +331A with a BRCA1BRCA2 mutation was associated with multiple BC events compared to +331A or BRCA1/BRCA2 alone, p=0.02. Conclusions: The PRP are risk factors for familial BC/OC, and +331A allele is a gene modifier of BRCA1 and BRCA2.