Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that and are ta...

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Published in:Oncotarget 2017-09, Vol.8 (39), p.64670-64684
Main Authors: Glubb, Dylan M, Johnatty, Sharon E, Quinn, Michael C J, O'Mara, Tracy A, Tyrer, Jonathan P, Gao, Bo, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Thompson, Pamela J, Dörk, Thilo, Dürst, Matthias, Modungo, Francesmary, Moysich, Kirsten, Heitz, Florian, du Bois, Andreas, Pfisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y, Lester, Jenny, Goode, Ellen L, Cunningham, Julie M, Winham, Stacey J, Larson, Melissa C, McCauley, Bryan M, Kjær, Susanne Krüger, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Salvesen, Helga B, Bjorge, Line, Webb, Penny M, Grant, Peter, Pejovic, Tanja, Moffitt, Melissa, Hogdall, Claus K, Hogdall, Estrid, Paul, James, Glasspool, Rosalind, Bernardini, Marcus, Tone, Alicia, Huntsman, David, Woo, Michelle, Group, Aocs, deFazio, Anna, Kennedy, Catherine J, Pharoah, Paul D P, MacGregor, Stuart, Chenevix-Trench, Georgia
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Language:English
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Summary:We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that and are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, and expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.18501