Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.
Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.
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DOI：
10.1158/1055-9965.epi-15-0363
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Zheng W
中科院分区：
文献类型：
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作者：
Guo X;Long J;Zeng C;Michailidou K;Ghoussaini M;Bolla MK;Wang Q;Milne RL;Shu XO;Cai Q;Beesley J;Kar SP;Andrulis IL;Anton-Culver H;Arndt V;Beckmann MW;Beeghly-Fadiel A;Benitez J;Blot W;Bogdanova N;Bojesen SE;Brauch H;Brenner H;Brinton L;Broeks A;Brüning T;Burwinkel B;Cai H;Canisius S;Chang-Claude J;Choi JY;Couch FJ;Cox A;Cross SS;Czene K;Darabi H;Devilee P;Droit A;Dörk T;Fasching PA;Fletcher O;Flyger H;Fostira F;Gaborieau V;García-Closas M;Giles GG;Grip M;Guénel P;Haiman CA;Hamann U;Hartman M;Hollestelle A;Hopper JL;Hsiung CN;Ito H;Jakubowska A;Johnson N;Kabisch M;Kang D;Khan S;Knight JA;Kosma VM;Lambrechts D;Le Marchand L;Li J;Lindblom A;Lophatananon A;Lubinski J;Mannermaa A;Manoukian S;Margolin S;Marme F;Matsuo K;McLean CA;Meindl A;Muir K;Neuhausen SL;Nevanlinna H;Nord S;Olson JE;Orr N;Peterlongo P;Putti TC;Rudolph A;Sangrajrang S;Sawyer EJ;Schmidt MK;Schmutzler RK;Shen CY;Shi J;Shrubsole MJ;Southey MC;Swerdlow A;Teo SH;Thienpont B;Toland AE;Tollenaar RA;Tomlinson IP;Truong T;Tseng CC;van den Ouweland A;Wen W;Winqvist R;Wu A;Yip CH;Zamora MP;Zheng Y;Hall P;Pharoah PD;Simard J;Chenevix-Trench G;kConFab Investigators;Dunning AM;Easton DF;Zheng W
最近的一项关联研究确定了4 q24的一个常见变异（rs 9790517）与乳腺癌风险相关。独立的关联信号和潜在的功能变异在这个位点还没有被探索。我们对来自乳腺癌协会联盟的55,540例乳腺癌病例和51,168例对照进行了精细映射分析。条件分析确定了欧洲血统女性中的两个独立关联信号，分别为rs 9790517（条件p = 2.51 × 10−4; OR = 1.04; 95%CI 1.02-1.07）和rs77928427（p = 1.86 × 10−4; OR = 1.04; 95%CI 1.02-1.07）。使用来自DNA元件百科全书（ENCODE）项目的数据的功能注释揭示了两个推定的功能变体，rs62331150和rs73838678与rs 9790517（r2 ≥ 0.90）处于连锁不平衡（LD），分别位于最近基因TET 2的活性启动子或增强子中。这两种变体都位于DNA酶I超敏反应和转录因子结合位点。使用来自癌症基因组图谱（TCGA）和乳腺癌国际联盟（METABRIC）分子分类学的数据，我们发现rs62331150与乳腺正常组织和肿瘤组织中TET 2的表达水平相关。我们的研究确定了4 q24与乳腺癌风险相关的两个独立关联信号，并表明在该位点观察到的关联可能通过调节TET 2介导。大样本量精细定位研究可用于确定乳腺癌风险的独立位点
A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 (conditional p = 2.51 × 10−4; OR = 1.04; 95% CI 1.02–1.07) and rs77928427 (p = 1.86 × 10−4; OR = 1.04; 95% CI 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.