Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
复制标题
DOI：
10.1038/ncomms5999
复制
发表时间：
2014-09-23
影响因子：
16.6
通讯作者：
Australian Ovarian Cancer Management Group
中科院分区：
文献类型：
--
作者：
Ghoussaini M;Edwards SL;Michailidou K;Nord S;Cowper-Sal Lari R;Desai K;Kar S;Hillman KM;Kaufmann S;Glubb DM;Beesley J;Dennis J;Bolla MK;Wang Q;Dicks E;Guo Q;Schmidt MK;Shah M;Luben R;Brown J;Czene K;Darabi H;Eriksson M;Klevebring D;Bojesen SE;Nordestgaard BG;Nielsen SF;Flyger H;Lambrechts D;Thienpont B;Neven P;Wildiers H;Broeks A;Van't Veer LJ;Th Rutgers EJ;Couch FJ;Olson JE;Hallberg E;Vachon C;Chang-Claude J;Rudolph A;Seibold P;Flesch-Janys D;Peto J;Dos-Santos-Silva I;Gibson L;Nevanlinna H;Muranen TA;Aittomäki K;Blomqvist C;Hall P;Li J;Liu J;Humphreys K;Kang D;Choi JY;Park SK;Noh DY;Matsuo K;Ito H;Iwata H;Yatabe Y;Guénel P;Truong T;Menegaux F;Sanchez M;Burwinkel B;Marme F;Schneeweiss A;Sohn C;Wu AH;Tseng CC;Van Den Berg D;Stram DO;Benitez J;Zamora MP;Perez JI;Menéndez P;Shu XO;Lu W;Gao YT;Cai Q;Cox A;Cross SS;Reed MW;Andrulis IL;Knight JA;Glendon G;Tchatchou S;Sawyer EJ;Tomlinson I;Kerin MJ;Miller N;Haiman CA;Henderson BE;Schumacher F;Le Marchand L;Lindblom A;Margolin S;Teo SH;Yip CH;Lee DS;Wong TY;Hooning MJ;Martens JW;Collée JM;van Deurzen CH;Hopper JL;Southey MC;Tsimiklis H;Kapuscinski MK;Shen CY;Wu PE;Yu JC;Chen ST;Alnæs GG;Borresen-Dale AL;Giles GG;Milne RL;McLean C;Muir K;Lophatananon A;Stewart-Brown S;Siriwanarangsan P;Hartman M;Miao H;Buhari SA;Teo YY;Fasching PA;Haeberle L;Ekici AB;Beckmann MW;Brenner H;Dieffenbach AK;Arndt V;Stegmaier C;Swerdlow A;Ashworth A;Orr N;Schoemaker MJ;García-Closas M;Figueroa J;Chanock SJ;Lissowska J;Simard J;Goldberg MS;Labrèche F;Dumont M;Winqvist R;Pylkäs K;Jukkola-Vuorinen A;Brauch H;Brüning T;Koto YD;Radice P;Peterlongo P;Bonanni B;Volorio S;Dörk T;Bogdanova NV;Helbig S;Mannermaa A;Kataja V;Kosma VM;Hartikainen JM;Devilee P;Tollenaar RA;Seynaeve C;Van Asperen CJ;Jakubowska A;Lubinski J;Jaworska-Bieniek K;Durda K;Slager S;Toland AE;Ambrosone CB;Yannoukakos D;Sangrajrang S;Gaborieau V;Brennan P;McKay J;Hamann U;Torres D;Zheng W;Long J;Anton-Culver H;Neuhausen SL;Luccarini C;Baynes C;Ahmed S;Maranian M;Healey CS;González-Neira A;Pita G;Alonso MR;Alvarez N;Herrero D;Tessier DC;Vincent D;Bacot F;de Santiago I;Carroll J;Caldas C;Brown MA;Lupien M;Kristensen VN;Pharoah PD;Chenevix-Trench G;French JD;Easton DF;Dunning AM;Australian Ovarian Cancer Management Group;Australian Ovarian Cancer Management Group
Gwas在2q35上发现了一个乳腺癌易感基因。在这里，我们报告了使用来自50个病例对照研究的101,943名受试者的数据对该基因座的精细定位。我们使用‘iCOGS’基因分型阵列对276个SNP进行了分型，并使用1000个基因组计划数据对另外1,284个SNPs进行了分型。除了两个强相关的SNPs(rs4442975G/T和rs6721996G/A)外，所有这些SNPs都被排除为候选的因果变异，与>；100：1的比例一致。最佳功能候选基因rs4442975与雌激素受体阳性(ER+)疾病相关，在欧洲人中，每个t等位基因的优势比(OR)为0.85(95%可信区间=0.84−0.87；P=1.7×10−43)。该SNP位于转录增强子的两侧，该转录增强子与Ig fbp5(编码胰岛素样生长因子结合蛋白5)的启动子物理上相互作用，并显示出等位基因特异性的基因表达、FOXA1结合和染色质循环。有证据表明，g等位基因通过相对下调Igfbp5基因而增加乳腺癌的易感性，Igfbp5基因在乳腺细胞生物学中具有已知的作用。此前的研究发现，2q35基因座与乳腺癌之间存在关联。在这里，作者证明了位于2q35的SNP rs4442975与雌激素受体阳性疾病有关，并认为这种影响是通过下调已知的乳腺癌基因Igfbp5来实现的。
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology. Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.
登录
查看更多内容
影响因子：
4.4
作者：
Li, BH;Kadura, I;Watson, DE
通讯作者：
Watson, DE
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
4
作者：
Sureshbabu, Angara;Okajima, Hiroshi;Flint, David
通讯作者：
Flint, David
影响因子：
10.3
作者：
Ghoussaini, Maya;Song, Honglin;Dunning, Alison M.
通讯作者：
Dunning, Alison M.
影响因子：
4.8
作者：
Tripathi, Gyanendra;Salih, Dervis A. M.;Pell, Jennifer M.
通讯作者：
Pell, Jennifer M.