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

Journal article


Publication Details

Author(s): 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 PA, 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
Journal: American Journal of Human Genetics
Publication year: 2016
Volume: 99
Journal issue: 4
Pages range: 903-911
ISSN: 0002-9297


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.


FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe


External institutions with authors

Aichi Cancer Center Research Institute
Antoni van Leeuwenhoek
Cancer Council Victoria
Cancer Research Initiatives Foundation (CARIF)
China Medical University (CMU) / 中國醫藥大學
City of Hope Medical Center
Copenhagen University Hospital
Deutsches Krebsforschungszentrum (DKFZ)
École Polytechnique - Université Paris-Saclay
Erasmus University Medical Center
European Institute of Oncology / Istituto Europeo di Oncologia (IEO)
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Hannover Medical School / Medizinische Hochschule Hannover (MHH)
Helsingin yliopisto / University of Helsinki
International Agency for Research on Cancer (IARC)
Istituto di ricovero e cura a carattere scientifico (IRCCS)
Kaohsiung Medical University (KMU) / 高雄醫學大學
Karolinska Institute
King’s College London
Leiden University
Mayo Clinic
McGill University
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
National University of Singapore (NUS)
Oslo University Hospital / Oslo Universitetssykehus
Oulun Yliopisto / University of Oulo
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruprecht-Karls-Universität Heidelberg
Seoul National University (SNU) / 서울대학교
Shanghai Center For Disease Control And Prevention (SCDC)
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
Technische Universität München (TUM)
The Institute of Cancer Research (ICR)
The University of Melbourne
Universitätsklinikum Köln
Université Laval (UL)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Eastern Finland
University of Hawaii (U.H.)
University of Malaya (UM) / Universiti Malaya
University of Manchester
University of Oxford
University of Sheffield
University of Southern California (USC)
Vanderbilt University


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: 

Last updated on 2019-16-01 at 06:02