Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.
Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.
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DOI：
10.1038/ng.3650
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发表时间：
2016-10
期刊：
影响因子：
30.8
通讯作者：
Lupien, Mathieu
中科院分区：
文献类型：
--
作者：
Bailey, Swneke D.;Desai, Kinjal;Kron, Ken J.;Mazrooei, Parisa;Sinnott-Armstrong, Nicholas A.;Treloar, Aislinn E.;Dowar, Mark;Thu, Kelsie L.;Cescon, David W.;Silvester, Jennifer;Yang, S. Y. Cindy;Wu, Xue;Pezo, Rossanna C.;Haibe-Kains, Benjamin;Mak, Tak W.;Bedard, Philippe L.;Pugh, Trevor J.;Sallari, Richard C.;Lupien, Mathieu
雌激素受体α（ESR1）的持续表达驱动了三分之二的乳腺癌，并定义了ESR1阳性亚型。ESR1在雌激素刺激后参与增强子以建立致癌表达程序。涉及ESR1基因的体细胞拷贝数改变发生在约1%的ESR1阳性乳腺癌中，这意味着ESR1持续表达的其他机制。我们报告了在7%的ESR1阳性乳腺癌中，调节ESR1的调控元件（SRE）组中体细胞突变的显著富集。这些突变通过调节转录因子与DNA的结合来调节ESR1的表达。SRE包括一个反复突变的增强子，其活性也受到功能性遗传单核苷酸变体（SNV）rs9383590的影响，该变体负责几个乳腺癌风险基因座。我们的工作强调了将调控元件的组合活性作为一个单元来描述非编码基因改变对癌症中单个基因的影响的重要性。
Sustained expression of the oestrogen receptor alpha (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon oestrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, implying that other mechanisms underlie the persistent expression of ESR1. We report the significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by a functional inherited single nucleotide variant (SNV) rs9383590 that accounts for several breast cancer risk-loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
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影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
30.8
作者：
Dunning AM;Michailidou K;Kuchenbaecker KB;Thompson D;French JD;Beesley J;Healey CS;Kar S;Pooley KA;Lopez-Knowles E;Dicks E;Barrowdale D;Sinnott-Armstrong NA;Sallari RC;Hillman KM;Kaufmann S;Sivakumaran H;Moradi Marjaneh M;Lee JS;Hills M;Jarosz M;Drury S;Canisius S;Bolla MK;Dennis J;Wang Q;Hopper JL;Southey MC;Broeks A;Schmidt MK;Lophatananon A;Muir K;Beckmann MW;Fasching PA;Dos-Santos-Silva I;Peto J;Sawyer EJ;Tomlinson I;Burwinkel B;Marme F;Guénel P;Truong T;Bojesen SE;Flyger H;González-Neira A;Perez JI;Anton-Culver H;Eunjung L;Arndt V;Brenner H;Meindl A;Schmutzler RK;Brauch H;Hamann U;Aittomäki K;Blomqvist C;Ito H;Matsuo K;Bogdanova N;Dörk T;Lindblom A;Margolin S;Kosma VM;Mannermaa A;Tseng CC;Wu AH;Lambrechts D;Wildiers H;Chang-Claude J;Rudolph A;Peterlongo P;Radice P;Olson JE;Giles GG;Milne RL;Haiman CA;Henderson BE;Goldberg MS;Teo SH;Yip CH;Nord S;Borresen-Dale AL;Kristensen V;Long J;Zheng W;Pylkäs K;Winqvist R;Andrulis IL;Knight JA;Devilee P;Seynaeve C;Figueroa J;Sherman ME;Czene K;Darabi H;Hollestelle A;van den Ouweland AM;Humphreys K;Gao YT;Shu XO;Cox A;Cross SS;Blot W;Cai Q;Ghoussaini M;Perkins BJ;Shah M;Choi JY;Kang D;Lee SC;Hartman M;Kabisch M;Torres D;Jakubowska A;Lubinski J;Brennan P;Sangrajrang S;Ambrosone CB;Toland AE;Shen CY;Wu PE;Orr N;Swerdlow A;McGuffog L;Healey S;Lee A;Kapuscinski M;John EM;Terry MB;Daly MB;Goldgar DE;Buys SS;Janavicius R;Tihomirova L;Tung N;Dorfling CM;van Rensburg EJ;Neuhausen SL;Ejlertsen B;Hansen TV;Osorio A;Benitez J;Rando R;Weitzel JN;Bonanni B;Peissel B;Manoukian S;Papi L;Ottini L;Konstantopoulou I;Apostolou P;Garber J;Rashid MU;Frost D;EMBRACE;Izatt L;Ellis S;Godwin AK;Arnold N;Niederacher D;Rhiem K;Bogdanova-Markov N;Sagne C;Stoppa-Lyonnet D;Damiola F;GEMO Study Collaborators;Sinilnikova OM;Mazoyer S;Isaacs C;Claes KB;De Leeneer K;de la Hoya M;Caldes T;Nevanlinna H;Khan S;Mensenkamp AR;HEBON;Hooning MJ;Rookus MA;Kwong A;Olah E;Diez O;Brunet J;Pujana MA;Gronwald J;Huzarski T;Barkardottir RB;Laframboise R;Soucy P;Montagna M;Agata S;Teixeira MR;kConFab Investigators;Park SK;Lindor N;Couch FJ;Tischkowitz M;Foretova L;Vijai J;Offit K;Singer CF;Rappaport C;Phelan CM;Greene MH;Mai PL;Rennert G;Imyanitov EN;Hulick PJ;Phillips KA;Piedmonte M;Mulligan AM;Glendon G;Bojesen A;Thomassen M;Caligo MA;Yoon SY;Friedman E;Laitman Y;Borg A;von Wachenfeldt A;Ehrencrona H;Rantala J;Olopade OI;Ganz PA;Nussbaum RL;Gayther SA;Nathanson KL;Domchek SM;Arun BK;Mitchell G;Karlan BY;Lester J;Maskarinec G;Woolcott C;Scott C;Stone J;Apicella C;Tamimi R;Luben R;Khaw KT;Helland Å;Haakensen V;Dowsett M;Pharoah PD;Simard J;Hall P;García-Closas M;Vachon C;Chenevix-Trench G;Antoniou AC;Easton DF;Edwards SL
通讯作者：
Edwards SL
影响因子：
64.8
作者：
Sanyal, Amartya;Lajoie, Bryan R.;Jain, Gaurav;Dekker, Job
通讯作者：
Dekker, Job
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
Li Q;Seo JH;Stranger B;McKenna A;Pe'er I;Laframboise T;Brown M;Tyekucheva S;Freedman ML
通讯作者：
Freedman ML