title: The 5p12 breast cancer susceptibility locus affects MRPS30 expression in estrogen-receptor positive tumors.
abstract: Genome-wide association studies have identified numerous loci linked to breast cancer susceptibility, but the mechanism by which variations at these loci influence susceptibility is usually unknown. Some variants are only associated with particular clinical subtypes of breast cancer. Understanding how and why these variants influence subtype-specific cancer risk contributes to our understanding of cancer etiology. We conducted a genome-wide expression Quantitative Trait Locus (eQTL) study in a discovery set of 287 breast tumors and 97 normal mammary tissue samples and a replication set of 235 breast tumors. We found that the risk-associated allele of rs7716600 in the 5p12 estrogen receptor-positive (ER-positive) susceptibility locus was associated with elevated expression of the nearby gene MRPS30 exclusively in ER-positive tumors. We replicated this finding in 235 independent tumors. Further, we showed the rs7716600 risk genotype was associated with decreased MRPS30 promoter methylation exclusively in ER-positive breast tumors. In vitro studies in MCF-7 cells carrying the protective genotype showed that estrogen stimulation decreased MRPS30 promoter chromatin availability and mRNA levels. In contrast, in 600MPE cells carrying the risk genotype, estrogen increased MRPS30 expression and did not affect promoter availability. Our data suggest the 5p12 risk allele affects MRPS30 expression in estrogen-responsive tumor cells after tumor initiation by a mechanism affecting chromatin availability. These studies emphasize that the genetic architecture of breast cancer is context-specific, and integrated analysis of gene expression and chromatin remodeling in normal and tumor tissues will be required to explain the mechanisms of risk alleles.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, USA. Electronic address: dquigley@cc.ucsf.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.affiliation: Breast Cancer Research Group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway, (NCMM), University of Oslo, Norway. Electronic address: elisa.fiorito@ncmm.uio.no.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fiorito
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: silje.nord@rr-research.no.
authors.forename: Silje
authors.initials: S
authors.lastname: Nord
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton UK; Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium. Electronic address: pvl@sanger.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: Grethe.I.Grenaker.Alnas@rr-research.no.
authors.forename: Grethe Grenaker
authors.initials: GG
authors.lastname: Alnæs
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: thofle@rr-research.no.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleischer
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset, Centre Etude Polymorphism Humain, (CEPH), Paris, France; Laboratory of Epigenetics, Centre National de Génotypage, Commissariat à l'énergie Atomique et, aux énergies Alternatives (CEA)-Institut de Génomique, Evry, France. Electronic address: tost@cng.fr.
authors.forename: Jorg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: Hans.Kristian.Moen.Vollan@rr-research.no.
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Moen Vollan
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: TRAMM@ONCOLOGY.DK.
authors.forename: Trine
authors.initials: T
authors.lastname: Tramm
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: jens@oncology.dk.
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.affiliation: Department of Breast-Endocrine Surgery, Akershus University Hospital, Oslo, Norway; Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway. Electronic address: i.r.k.bukholm@medisin.uio.no.
authors.forename: Ida R
authors.initials: IR
authors.lastname: Bukholm
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Breast Cancer Research Group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway, (NCMM), University of Oslo, Norway. Electronic address: a.h.rodriguez@ncmm.uio.no.
authors.forename: Antoni
authors.initials: A
authors.lastname: Hurtado
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, USA. Electronic address: abalmain@cc.ucsf.edu.
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: a.l.borresen-dale@medisin.uio.no.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway. Electronic address: Vessela.N.Kristensen@rr-research.no.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D040641:Quantitative Trait Loci; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D011960:Receptors, Estrogen
keywords: Breast cancer; Estrogen; Expression Quantitative Trait Locus; Genetics; chromatin