Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

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• 作者：Juliet D. French¹ ; ¹³¹ ; Maya Ghoussaini² ; ¹³¹ ; Stacey L. Edwards¹ ; ¹³¹ ; Kerstin B. Meyer³ ; ¹³¹ ; Kyriaki Michailidou⁴ ; Shahana Ahmed² ; Sofia Khan⁵ ; Mel J. Maranian² ; Martin O&rsquo ; Reilly³ ; Kristine M. Hillman¹ ; Joshua A. Betts¹ ; Thomas Carroll³ ; Peter J. Bailey¹ ; Ed Dicks² ; Jonathan Beesley⁶ ; Jonathan Tyrer² ; Ana-Teresa Maia³ ; Andrew Beck⁷ ; Nicholas W. Knoblauch⁷ ; Constance Chen⁸ ; Peter Kraft⁸ ; ⁹ ; Daniel Barnes⁴ ; Anna Gonzá ; lez-Neira¹⁰ ; M. Rosario Alonso¹⁰ ; Daniel Herrero¹⁰ ; Daniel C. Tessier¹¹ ; Daniel Vincent¹¹ ; Francois Bacot¹¹ ; Craig Luccarini² ; Caroline Baynes² ; Don Conroy² ; Joe Dennis⁴ ; Manjeet K. Bolla⁴ ; Qin Wang⁴ ; John L. Hopper¹² ; Melissa C. Southey¹³ ; Marjanka K. Schmidt¹⁴ ; ¹⁵ ; Annegien Broeks¹⁵ ; Senno Verhoef¹⁶ ; Sten Cornelissen¹⁵ ; Kenneth Muir¹⁷ ; Artitaya Lophatananon¹⁷ ; Sarah Stewart-Brown¹⁷ ; Pornthep Siriwanarangsan¹⁸ ; Peter A. Fasching¹⁹ ; ²⁰ ; Christian R. Loehberg²⁰ ; Arif B. Ekici²¹ ; Matthias W. Beckmann²⁰ ; Julian Peto²² ; Isabel dos Santos Silva²² ; Nichola Johnson²³ ; Zoe Aitken²² ; Elinor J. Sawyer²⁴ ; Ian Tomlinson²⁵ ; Michael J. Kerin²⁶ ; Nicola Miller²⁶ ; Frederik Marme²⁷ ; ²⁸ ; Andreas Schneeweiss²⁷ ; ²⁸ ; Christof Sohn²⁷ ; Barbara Burwinkel²⁷ ; ²⁹ ; Pascal Gué ; nel³⁰ ; ³¹ ; Thé ; rè ; se Truong³⁰ ; ³¹ ; Pierre Laurent-Puig³² ; Florence Menegaux³⁰ ; ³¹ ; Stig E. Bojesen³³ ; ³⁴ ; Bø ; rge G. Nordestgaard³³ ; ³⁴ ; Sune F. Nielsen³³ ; ³⁴ ; Henrik Flyger³⁵ ; Roger L. Milne³⁶ ; M. Pilar Zamora³⁷ ; Jose Ignacio Arias Perez³⁸ ; Javier Benitez¹⁰ ; ³⁹ ; Hoda Anton-Culver⁴⁰ ; Hermann Brenner⁴¹ ; Heiko Mü ; ller⁴¹ ; Volker Arndt⁴¹ ; Christa Stegmaier⁴² ; Alfons Meindl⁴³ ; Peter Lichtner⁴⁴ ; Rita K. Schmutzler⁴⁵ ; Christoph Engel⁴⁶ ; Hiltrud Brauch⁴⁷ ; ⁴⁸ ; Ute Hamann⁴⁹ ; Christina Justenhoven⁴⁷ ; ⁴⁸ ; The GENICA Network ⁴⁷ ; ⁴⁸ ; ⁴⁹ ; ⁵⁰ ; ⁵¹ ; ⁵² ; ⁵³
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：92
• 期：4
• 页码：489-503
• 全文大小：1305 K

文摘

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.