Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, Hillman KM, Kaufmann S, Sivakumaran H, Marjaneh MM, Lee JS, Dennis J, Bolla MK, Wang Q, Dicks E, Milne RL, Hopper JL, Southey MC, Schmidt MK, Broeks A, Muir K, Lophatananon A, Fasching P, Beckmann M, Fletcher O, Johnson N, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guenel P, Truong T, Bojesen SE, Flyger H, Benitez J, Gonzalez-Neira A, Alonso R, Pita G, Neuhausen SL, Anton-Culver H, Brenner H, Arndt V, Meindl A, Schmutzler RK, Brauch H, Hamann U, Tessier DC, Vincent D, Nevanlinna H, Khan S, Matsuo K, Ito H, Dork T, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Wu AH, Van Den Berg D, Lambrechts D, Floris G, Chang-Claude J, Rudolph A, Radice P, Barile M, Couch FJ, Hallberg E, Giles GG, Haiman CA, Le Marchand L, Goldberg MS, Teo SH, Yip CH, Borresen-Dale AL, Zheng W, Cai Q, Winqvist R, Pylkas K, Andrulis IL, Devilee P, Tollenaar RAEM, Garcia-Closas M, Figueroa J, Hall P, Czene K, Brand JS, Darabi H, Eriksson M, Hooning MJ, Koppert LB, Li J, Shu XO, Zheng Y, Cox A, Cross SS, Shah M, Rhenius V, Choi JY, Kang D, Hartman M, Chia KS, Kabisch M, Torres D, Luccarini C, Conroy DM, Jakubowska A, Lubinski J, Sangrajrang S, Brennan P, Olswold C, Slager S, Shen CY, Hou MF, Swerdlow A, Schoemaker MJ, Simard J, Pharoah PDP, Kristensen V, Chenevix-Trench G, Easton DF, Dunning AM, Edwards SL (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 99

Pages Range: 903-911

Journal Issue: 4

DOI: 10.1016/j.ajhg.2016.07.017

Abstract

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 × 10-30). 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 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+= 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). 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.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Antoni van Leeuwenhoek Netherlands (NL) Cancer Council Victoria Australia (AU) The University of Melbourne Australia (AU) University of Manchester United Kingdom (GB) The Institute of Cancer Research (ICR) United Kingdom (GB) King’s College London United Kingdom (GB) University of Oxford United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) École Polytechnique - Université Paris-Saclay France (FR) Copenhagen University Hospital Denmark (DK) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) City of Hope Medical Center United States (USA) (US) University of California Irvine United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Köln Germany (DE) McGill University Canada (CA) Helsingin yliopisto / University of Helsinki Finland (FI) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Mayo Clinic United States (USA) (US) University of Malaya (UM) / Universiti Malaya Malaysia (MY) Vanderbilt University United States (USA) (US) Oulun Yliopisto / University of Oulo Finland (FI) National Cancer Institute (NCI) United States (USA) (US) Karolinska Institute Sweden (SE) Erasmus University Medical Center (MC) Netherlands (NL) Shanghai Center For Disease Control And Prevention (SCDC) China (CN) Aichi Cancer Center Research Institute Japan (JP) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Eastern Finland Finland (FI) University of Southern California (USC) United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) University of Hawaii (U.H.) United States (USA) (US) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Mount Sinai Hospital (MSH) Canada (CA) Leiden University Netherlands (NL) University of Sheffield United Kingdom (GB) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) National University of Singapore (NUS) Singapore (SG) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) International Agency for Research on Cancer (IARC) France (FR) China Medical University (CMU) / 中國醫藥大學 Taiwan (TW) Kaohsiung Medical University (KMU) / 高雄醫學大學 Taiwan (TW) Université Laval (UL) Canada (CA)

How to cite

APA:

Ghoussaini, M., French, J.D., Michailidou, K., Nord, S., Beesley, J., Canisus, S.,... Edwards, S.L. (2016). Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. American Journal of Human Genetics, 99(4), 903-911. https://dx.doi.org/10.1016/j.ajhg.2016.07.017

MLA:

Ghoussaini, Maya, et al. "Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation." American Journal of Human Genetics 99.4 (2016): 903-911.

BibTeX: Download