Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Authors:
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
Dr Dylan Glubb, PhD
Dr Dylan Glubb, PhD
QIMR Berghofer Medical Research Institute
Brisbane, QLD | Australia
Dieter Flesch-Janys
Dieter Flesch-Janys
United Kingdom
Maya Ghoussaini Stacey L Edwards Kyriaki Michailidou Silje Nord Richard Cowper-Sal Lari Kinjal Desai Siddhartha Kar Kristine M Hillman Susanne Kaufmann Dylan M Glubb Jonathan Beesley Joe Dennis Manjeet K Bolla Qin Wang Ed Dicks Qi Guo Marjanka K Schmidt Mitul Shah Robert Luben Judith Brown Kamila Czene Hatef Darabi Mikael Eriksson Daniel Klevebring Stig E Bojesen Børge G Nordestgaard Sune F Nielsen Henrik Flyger Diether Lambrechts Bernard Thienpont Patrick Neven Hans Wildiers Annegien Broeks Laura J Van't Veer Emiel J Th Rutgers Fergus J Couch Janet E Olson Emily Hallberg Celine Vachon Jenny Chang-Claude Anja Rudolph Petra Seibold Julian Peto Isabel Dos-Santos-Silva Lorna Gibson Heli Nevanlinna Taru A Muranen Kristiina Aittomäki Carl Blomqvist Per Hall Jingmei Li Jianjun Liu Keith Humphreys Daehee Kang Ji-Yeob Choi Sue K Park Dong-Young Noh Keitaro Matsuo Hidemi Ito Hiroji Iwata Yasushi Yatabe Pascal Guénel Thérèse Truong Florence Menegaux Marie Sanchez Barbara Burwinkel Frederik Marme Andreas Schneeweiss Christof Sohn Anna H Wu Chiu-Chen Tseng David Van Den Berg Daniel O Stram Javier Benitez M Pilar Zamora Jose Ignacio Arias Perez Primitiva Menéndez Xiao-Ou Shu Wei Lu Yu-Tang Gao Qiuyin Cai Angela Cox Simon S Cross Malcolm W R Reed Irene L Andrulis Julia A Knight Gord Glendon Sandrine Tchatchou Elinor J Sawyer Ian Tomlinson Michael J Kerin Nicola Miller Christopher A Haiman Brian E Henderson Fredrick Schumacher Loic Le Marchand Annika Lindblom Sara Margolin Soo Hwang Teo Cheng Har Yip Daphne S C Lee Tien Y Wong Maartje J Hooning John W M Martens J Margriet Collée Carolien H M van Deurzen John L Hopper Melissa C Southey Helen Tsimiklis Miroslav K Kapuscinski Chen-Yang Shen Pei-Ei Wu Jyh-Cherng Yu Shou-Tung Chen Grethe Grenaker Alnæs Anne-Lise Borresen-Dale Graham G Giles Roger L Milne Catriona McLean Kenneth Muir Artitaya Lophatananon Sarah Stewart-Brown Pornthep Siriwanarangsan Mikael Hartman Hui Miao Shaik Ahmad Bin Syed Buhari Yik Ying Teo Peter A Fasching Lothar Haeberle Arif B Ekici Matthias W Beckmann Hermann Brenner Aida Karina Dieffenbach Volker Arndt Christa Stegmaier Anthony Swerdlow Alan Ashworth Nick Orr Minouk J Schoemaker Montserrat García-Closas Stephen J Chanock Jolanta Lissowska Jacques Simard Mark S Goldberg France Labrèche Martine Dumont Robert Winqvist Katri Pylkäs Arja Jukkola-Vuorinen Hiltrud Brauch Thomas Brüning Yon-Dschun Koto Paolo Radice Paolo Peterlongo Bernardo Bonanni Sara Volorio Thilo Dörk Natalia V Bogdanova Sonja Helbig Arto Mannermaa Vesa Kataja Veli-Matti Kosma Jaana M Hartikainen Peter Devilee Robert A E M Tollenaar Caroline Seynaeve Christi J Van Asperen Anna Jakubowska Jan Lubinski Katarzyna Jaworska-Bieniek Katarzyna Durda Susan Slager Amanda E Toland Christine B Ambrosone Drakoulis Yannoukakos Suleeporn Sangrajrang Valerie Gaborieau Paul Brennan James McKay Ute Hamann Diana Torres Wei Zheng Jirong Long Hoda Anton-Culver Susan L Neuhausen Craig Luccarini Caroline Baynes Shahana Ahmed Mel Maranian Catherine S Healey Anna González-Neira Guillermo Pita M Rosario Alonso Nuria Alvarez Daniel Herrero Daniel C Tessier Daniel Vincent Francois Bacot Ines de Santiago Jason Carroll Carlos Caldas Melissa A Brown Mathieu Lupien Vessela N Kristensen Paul D P Pharoah Georgia Chenevix-Trench Juliet D French Douglas F Easton Alison M Dunning

Nat Commun 2014 Sep 23;4:4999. Epub 2014 Sep 23.

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.

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.

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http://dx.doi.org/10.1038/ncomms5999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321900PMC
September 2014
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References

(Supplied by CrossRef)

SN Stacey et al.
Nat. Genet. 2007

RL Milne et al.
J. Natl Cancer Inst. 2009

SL Kong et al.
Mol. Syst. Biol. 2011

R Cowper-Sal lari et al.
Nat. Genet. 2012

LA Cirillo et al.
Mol. Cell 2002

A Hurtado et al.
Nat. Genet. 2011

O Corradin et al.
Genome Res. 2014

SL Edwards et al.
Am. J. Hum. Genet. 2013

K Michailidou et al.
Nat. Genet. 2013

M Ghoussaini et al.
J. Natl Cancer Inst. 2008

JD French et al.
Am. J. Hum. Genet. 2013

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