Five endometrial cancer risk loci identified through genome-wide association analysis.
Five endometrial cancer risk loci identified through genome-wide association analysis.
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DOI：
10.1038/ng.3562
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发表时间：
2016-06
期刊：
影响因子：
30.8
通讯作者：
Spurdle AB
中科院分区：
文献类型：
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作者：
Cheng TH;Thompson DJ;O'Mara TA;Painter JN;Glubb DM;Flach S;Lewis A;French JD;Freeman-Mills L;Church D;Gorman M;Martin L;National Study of Endometrial Cancer Genetics Group (NSECG);Hodgson S;Webb PM;Australian National Endometrial Cancer Study Group (ANECS);Attia J;Holliday EG;McEvoy M;Scott RJ;Henders AK;Martin NG;Montgomery GW;Nyholt DR;Ahmed S;Healey CS;Shah M;Dennis J;Fasching PA;Beckmann MW;Hein A;Ekici AB;Hall P;Czene K;Darabi H;Li J;Dörk T;Dürst M;Hillemanns P;Runnebaum I;Amant F;Schrauwen S;Zhao H;Lambrechts D;Depreeuw J;Dowdy SC;Goode EL;Fridley BL;Winham SJ;Njølstad TS;Salvesen HB;Trovik J;Werner HM;Ashton K;Otton G;Proietto T;Liu T;Mints M;Tham E;RENDOCAS;Consortium C;Jun Li M;Yip SH;Wang J;Bolla MK;Michailidou K;Wang Q;Tyrer JP;Dunlop M;Houlston R;Palles C;Hopper JL;AOCS Group;Peto J;Swerdlow AJ;Burwinkel B;Brenner H;Meindl A;Brauch H;Lindblom A;Chang-Claude J;Couch FJ;Giles GG;Kristensen VN;Cox A;Cunningham JM;Pharoah PDP;Dunning AM;Edwards SL;Easton DF;Tomlinson I;Spurdle AB
我们对三个子宫内膜癌GWAS和两个复制阶段进行了荟萃分析，共计7，737例子宫内膜癌病例和37，144例欧洲血统对照。全基因组插补和荟萃分析在染色体13q22.1上的可能调控区域确定了五个具有全基因组意义的新风险位点（rs 11841589，近KLF 5），6q22.31（rs 13328298，在LOC 643623中，靠近HEY 2和NCOA 7），8q24.21 15q15.1（rs 937213，在EIF 2AK 4中，靠近BMF）和14q32.33（rs 2498796，在AKT 1中，靠近SIVA 1）。对13q22.1基因座的功能研究表明，rs 9600103（与rs 11841589配对r2=0.98）位于与KLF 5启动子区相互作用的活性染色质区域。rs 9600103-T子宫内膜癌保护性等位基因在体外抑制基因表达，这表明与子宫发育相关的基因KLF 5表达的调节与肿瘤发生有关。这些发现为子宫内膜癌的遗传和生物学基础提供了更深入的了解。
We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.