Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 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
Maya Ghoussaini Juliet D French Kyriaki Michailidou Silje Nord Jonathan Beesley Sander Canisus Kristine M Hillman Susanne Kaufmann Haran Sivakumaran Mahdi Moradi Marjaneh Jason S Lee Joe Dennis Manjeet K Bolla Qin Wang Ed Dicks Roger L Milne John L Hopper Melissa C Southey Marjanka K Schmidt Annegien Broeks Kenneth Muir Artitaya Lophatananon Peter A Fasching Matthias W Beckmann Olivia Fletcher Nichola Johnson Elinor J Sawyer Ian Tomlinson Barbara Burwinkel Frederik Marme Pascal Guénel Thérèse Truong Stig E Bojesen Henrik Flyger Javier Benitez Anna González-Neira M Rosario Alonso Guillermo Pita Susan L Neuhausen Hoda Anton-Culver Hermann Brenner Volker Arndt Alfons Meindl Rita K Schmutzler Hiltrud Brauch Ute Hamann Daniel C Tessier Daniel Vincent Heli Nevanlinna Sofia Khan Keitaro Matsuo Hidemi Ito Thilo Dörk Natalia V Bogdanova Annika Lindblom Sara Margolin Arto Mannermaa Veli-Matti Kosma Anna H Wu David Van Den Berg Diether Lambrechts Giuseppe Floris Jenny Chang-Claude Anja Rudolph Paolo Radice Monica Barile Fergus J Couch Emily Hallberg Graham G Giles Christopher A Haiman Loic Le Marchand Mark S Goldberg Soo H Teo Cheng Har Yip Anne-Lise Borresen-Dale Wei Zheng Qiuyin Cai Robert Winqvist Katri Pylkäs Irene L Andrulis Peter Devilee Rob A E M Tollenaar Montserrat García-Closas Per Hall Kamila Czene Judith S Brand Hatef Darabi Mikael Eriksson Maartje J Hooning Linetta B Koppert Jingmei Li Xiao-Ou Shu Ying Zheng Angela Cox Simon S Cross Mitul Shah Valerie Rhenius Ji-Yeob Choi Daehee Kang Mikael Hartman Kee Seng Chia Maria Kabisch Diana Torres Craig Luccarini Don M Conroy Anna Jakubowska Jan Lubinski Suleeporn Sangrajrang Paul Brennan Curtis Olswold Susan Slager Chen-Yang Shen Ming-Feng Hou Anthony Swerdlow Minouk J Schoemaker Jacques Simard Paul D P Pharoah Vessela Kristensen Georgia Chenevix-Trench Douglas F Easton Alison M Dunning Stacey L Edwards

Am J Hum Genet 2016 Oct 15;99(4):903-911. Epub 2016 Sep 15.

Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address:

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER) breast cancer (per-g allele OR ER = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER) breast cancer (lead SNP rs6864776: per-a allele OR ER = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10), and a single signal 3 SNP (rs200229088: per-t allele OR ER = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

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http://dx.doi.org/10.1016/j.ajhg.2016.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065698PMC

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October 2016
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