Genome-wide association study of progression-free survival in ovarian cancer patients treated with carboplatin and paclitaxel identifies an enhancer that regulates three nearby genes. G. Chenevix-Trench1, Y. Lu1, J. Beesley1, K. Hillman1, S. Edwards1, S. Johnatty1, S. Macgregor1, B. Gao2, J. French1, A. deFazio2 on behalf of the Ovarian Cancer Association Consortium 1) QIMR Berghofer Medical Research Institute; 2) Department of Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Sydney, Australia.
Women diagnosed with advanced epithelial ovarian cancer are commonly treated with cytoreductive surgery followed by platinum/taxane chemotherapy, but there is considerable inter-individual variation in response. We have carried out a three-phase genome-wide association study of progression-free survival in a total of 1,053 serous ovarian cancer patients, from ten independent cohorts, with inclusion criteria that included uniform treatment with carboplatin and paclitaxel as first-line therapy. Fine mapping of our top region identified two rare SNPs in tight linkage disequilibrium in the TTC39B gene associated with progression free survival (P=1.2x10-7, Hazard Ratio = 2.5, 95%CI = 1.8 to 3.6). The minor allele of rs7874043 was associated with worse progression-free survival in all ten contributing sites, and there was no significant heterogeneity between sites. The minor allele was also associated with worse overall survival (P=5.6x10-3, Hazard Ratio = 1.75, 95%CI = 1.18 to 2.59). Through chromosome conformation capture and luciferase assays, we showed that the rare alleles (minor allele frequency = 0.02) that were associated with progression-free survival lie in an enhancer, and differentially interact with an alternative, but not the canonical, promoter of TTC39B. Common SNPs in TTC39B have previously been found to be associated with high density lipoprotein-cholesterol levels, so our findings suggest a possible role of cholesterol metabolism in serous ovarian cancer outcome. However, additional chromosome conformation capture experiments showed that the enhancer also interacts with the promoters of CCDC171 and PSIP1, which encodes a transcriptional co-activator. Luciferase assays are currently underway to confirm the role of the enhancer in regulating CCDC171 and PSIP1, and to determine which is the functional SNP.
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