Abstract POSTER-BIOL-1348: No association between PARK2 and BRCA1-associated gynecologic cancers

Abstract

Abstract Purpose of study: We sought to identify genomic modifiers of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. In a pilot study using the Illumina 610K Quad chip to perform a whole genome analysis of 592,532 single nucleotide polymorphisms (SNP), we found significant SNP genotype differences in the PARK2 gene between BRCA1 185delAG mutation carriers who developed gynecologic cancer (cases) compared to those who did not (controls). These SNPS created a haplotype structure that was present at four-times higher frequency in cases than controls (37% vs. 9%, p=0.0009). We hypothesized that PARK2, which has been shown to be mutated in other cancers and to have a tumor suppressive function, plays a role in the biology of BRCA1-associated gynecologic cancer development. Experimental Procedures: To validate a PARK2 risk haplotype in an independent dataset, we isolated germline DNA from 85 BRCA1 185delAG mutation carriers and used TaqMan SNP Genotyping to genotype seven SNPs in PARK2. To determine whether a correlation exits between the PARK2 risk haplotype and PARK2 expression levels in tissue, we quantified PARK2 expression in normal ovaries and ovarian cancer tissue using quantitative real-time PCR (qPCR). To determine the rate of PARK2 mutations in 17 BRCA1-associated ovarian cancers, we used a touchdown PCR protocol to amplify and sequence each PARK2 exon. To identify exon deletions and duplications in the PARK2 gene, we utilized the multiplex ligation-dependent probe amplification (MLPA) technique. Summary of Data: In an independent dataset of 85 BRCA1 185delAG mutation carriers, we found the PARK2 risk haplotype to be present in 35 (17%) of cases. The risk haplotype was present in a higher proportion of cancer cases than benign controls (6/12 or 50% vs. 29/73 or 8%), but this was not significant (p=0.54). We did not find a difference in PARK2 ovarian tissue expression levels in patients with and without the PARK2 risk haplotype. We sequenced the PARK2 gene and performed MPLA analysis from tumor DNA of 17 ovarian cancers from BRCA1 185delAG mutation carriers, but did not identify any deleterious PARK2 mutations or exon deletions and duplications. Conclusions: We did not validate a PARK2 risk haplotype as a modifier of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. We did not find evidence for PARK2 inactivation in BRCA1-associated gynecologic tumors. Citation Format: Christine Walsh, Hoorig Nassanian, Hasmik Agadjanian, Carl Miller, Sandra Orsulic, Beth Karlan. No association between PARK2 and BRCA1-associated gynecologic cancers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1348.