MicroRNA related polymorphisms and breast cancer risk.
Sofia Khan,
Dario Greco,
Kyriaki Michailidou,
Roger L Milne,
Taru A Muranen,
Tuomas Heikkinen,
Kirsimari Aaltonen,
Joe Dennis,
Manjeet K Bolla,
Jianjun Liu,
Per Hall,
Astrid Irwanto,
Keith Humphreys,
Jingmei Li,
Kamila Czene,
Jenny Chang-Claude,
Rebecca Hein,
Anja Rudolph,
Petra Seibold,
Dieter Flesch-Janys,
Olivia Fletcher,
Julian Peto,
Isabel dos Santos Silva,
Nichola Johnson,
Lorna Gibson,
Zoe Aitken,
John L Hopper,
Helen Tsimiklis,
Minh Bui,
Enes Makalic,
Daniel F Schmidt,
Melissa C Southey,
Carmel Apicella,
Jennifer Stone,
Quinten Waisfisz,
Hanne Meijers-Heijboer,
Muriel A Adank,
Rob B van der Luijt,
Alfons Meindl,
Rita K Schmutzler,
Bertram Müller-Myhsok,
Peter Lichtner,
Clare Turnbull,
Nazneen Rahman,
Stephen J Chanock,
David J Hunter,
Angela Cox,
Simon S Cross,
Malcolm W R Reed,
Marjanka K Schmidt,
Annegien Broeks,
Laura J Van't Veer,
Frans B Hogervorst,
Peter A Fasching,
Michael G Schrauder,
Arif B Ekici,
Matthias W Beckmann,
Stig E Bojesen,
Børge G Nordestgaard,
Sune F Nielsen,
Henrik Flyger,
Javier Benitez,
Pilar M Zamora,
Jose I A Perez,
Christopher A Haiman,
Brian E Henderson,
Fredrick Schumacher,
Loic Le Marchand,
Paul D P Pharoah,
Alison M Dunning,
Mitul Shah,
Robert Luben,
Judith Brown,
Fergus J Couch,
Xianshu Wang,
Celine Vachon,
Janet E Olson,
Diether Lambrechts,
Matthieu Moisse,
Robert Paridaens,
Marie-Rose Christiaens,
Pascal Guénel,
Thérèse Truong,
Pierre Laurent-Puig,
Claire Mulot,
Frederick Marme,
Barbara Burwinkel,
Andreas Schneeweiss,
Christof Sohn,
Elinor J Sawyer,
Ian Tomlinson,
Michael J Kerin,
Nicola Miller,
Irene L Andrulis,
Julia A Knight,
Sandrine Tchatchou,
Anna Marie Mulligan,
Thilo Dörk,
Natalia V Bogdanova,
Natalia N Antonenkova,
Hoda Anton-Culver,
Hatef Darabi,
Mikael Eriksson,
Montserrat Garcia-Closas,
Jonine Figueroa,
Jolanta Lissowska,
Louise Brinton,
Peter Devilee,
Robert A E M Tollenaar,
Caroline Seynaeve,
Christi J van Asperen,
Vessela N Kristensen,
,
,
Susan Slager,
Amanda E Toland,
Christine B Ambrosone,
Drakoulis Yannoukakos,
Annika Lindblom,
Sara Margolin,
Paolo Radice,
Paolo Peterlongo,
Monica Barile,
Paolo Mariani,
Maartje J Hooning,
John W M Martens,
J Margriet Collée,
Agnes Jager,
Anna Jakubowska,
Jan Lubinski,
Katarzyna Jaworska-Bieniek,
Katarzyna Durda,
Graham G Giles,
Catriona McLean,
Hiltrud Brauch,
Thomas Brüning,
Yon-Dschun Ko,
,
Hermann Brenner,
Aida Karina Dieffenbach,
Volker Arndt,
Christa Stegmaier,
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Michael Jones,
Jacques Simard,
Mark S Goldberg,
France Labrèche,
Martine Dumont,
Robert Winqvist,
Katri Pylkäs,
Arja Jukkola-Vuorinen,
Mervi Grip,
Vesa Kataja,
Veli-Matti Kosma,
Jaana M Hartikainen,
Arto Mannermaa,
Ute Hamann,
Georgia Chenevix-Trench,
Carl Blomqvist,
Kristiina Aittomäki,
Douglas F Easton,
Heli Nevanlinna
Abstract
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.