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
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
Oncotarget. 2017 Jun 15;8(39):64670-64684. doi: 10.18632/oncotarget.18501. eCollection 2017 Sep 12.
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 (<1×10). Larger patient numbers will be needed to convincingly identify any true associations at these loci.
我们之前在五个基因位点发现了与卵巢癌预后相关的联系。为了确定可能的因果基因变异和靶基因，我们优先选择了两个卵巢癌预后位点（1q22和19p12）进行进一步研究。生物信息学和功能遗传学分析表明，[具体基因1]和[具体基因2]分别是1q22和19p12处候选预后变异的靶基因。在19p12处，一个假定调控元件与[具体基因2]启动子区域的染色质相互作用与候选预后变异相关。在1q22处，假定调控元件增强了[具体基因1]启动子活性，且含有候选预后变异的单倍型调节了这些效应。在一个公共数据集中，[具体基因1]和[具体基因2]的表达均与卵巢癌无进展生存期或总生存时间相关。在一组扩大的6162例上皮性卵巢癌患者中，我们发现1q22和19p12位点的功能性候选基因以及其他区域变异与患者预后存在名义上的关联；然而，没有任何关联达到我们的统计学显著性阈值（<1×10）。需要更大的患者样本量才能令人信服地确定这些位点的任何真实关联。
