title: Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.
abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
authors: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada.
authors: Yosr
authors: Y
authors: Hamdi
authors: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada.
authors: Penny
authors: P
authors: Soucy
authors: Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France.|Centre National de la Recherche Scientifique, Toulouse, France.|Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors: Véronique
authors: V
authors: Adoue
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors: Kyriaki
authors: K
authors: Michailidou
authors: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors: Sander
authors: S
authors: Canisius
authors: Centre de Recherche du CHU de Québec - Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Université Laval, Quebec, Canada.
authors: Audrey
authors: A
authors: Lemaçon
authors: Centre de Recherche du CHU de Québec - Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Université Laval, Quebec, Canada.
authors: Arnaud
authors: A
authors: Droit
authors: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors: Irene L
authors: IL
authors: Andrulis
authors: Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
authors: Hoda
authors: H
authors: Anton-Culver
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors: Volker
authors: V
authors: Arndt
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Caroline
authors: C
authors: Baynes
authors: Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors: Carl
authors: C
authors: Blomqvist
authors: Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.|Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors: Natalia V
authors: NV
authors: Bogdanova
authors: Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Stig E
authors: SE
authors: Bojesen
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Manjeet K
authors: MK
authors: Bolla
authors: Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
authors: Bernardo
authors: B
authors: Bonanni
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors: Anne-Lise
authors: AL
authors: Borresen-Dale
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Judith S
authors: JS
authors: Brand
authors: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.|German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
authors: Hiltrud
authors: H
authors: Brauch
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.|German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
authors: Hermann
authors: H
authors: Brenner
authors: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors: Annegien
authors: A
authors: Broeks
authors: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
authors: Barbara
authors: B
authors: Burwinkel
authors: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.|University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Jenny
authors: J
authors: Chang-Claude
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Fergus J
authors: FJ
authors: Couch
authors: Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors: Angela
authors: A
authors: Cox
authors: Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
authors: Simon S
authors: SS
authors: Cross
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Kamila
authors: K
authors: Czene
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Hatef
authors: H
authors: Darabi
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Joe
authors: J
authors: Dennis
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Peter
authors: P
authors: Devilee
authors: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
authors: Thilo
authors: T
authors: Dörk
authors: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors: Isabel
authors: I
authors: Dos-Santos-Silva
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Mikael
authors: M
authors: Eriksson
authors: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.|David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
authors: Peter A
authors: PA
authors: Fasching
authors: Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.|Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors: Jonine
authors: J
authors: Figueroa
authors: Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors: Henrik
authors: H
authors: Flyger
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors: Montserrat
authors: M
authors: García-Closas
authors: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: Department of Medicine, McGill University, Montreal, Canada.|Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
authors: Mark S
authors: MS
authors: Goldberg
authors: Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Anna
authors: A
authors: González-Neira
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors: Grethe
authors: G
authors: Grenaker-Alnæs
authors: Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, VilleJuif, France.
authors: Pascal
authors: P
authors: Guénel
authors: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
authors: Lothar
authors: L
authors: Haeberle
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Christopher A
authors: CA
authors: Haiman
authors: Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
authors: Ute
authors: U
authors: Hamann
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Emily
authors: E
authors: Hallberg
authors: Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors: Maartje J
authors: MJ
authors: Hooning
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
authors: John L
authors: JL
authors: Hopper
authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors: Anna
authors: A
authors: Jakubowska
authors: Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK.
authors: Michael
authors: M
authors: Jones
authors: Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
authors: Maria
authors: M
authors: Kabisch
authors: Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland.
authors: Vesa
authors: V
authors: Kataja
authors: Vesalius Research Center, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
authors: Diether
authors: D
authors: Lambrechts
authors: University of Hawaii Cancer Center, Honolulu, HI, USA.
authors: Loic
authors: L
authors: Le Marchand
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors: Annika
authors: A
authors: Lindblom
authors: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors: Jan
authors: J
authors: Lubinski
authors: Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Arto
authors: A
authors: Mannermaa
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Mel
authors: M
authors: Maranian
authors: Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Sara
authors: S
authors: Margolin
authors: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Frederik
authors: F
authors: Marme
authors: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
authors: Roger L
authors: RL
authors: Milne
authors: Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors: Susan L
authors: SL
authors: Neuhausen
authors: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors: Heli
authors: H
authors: Nevanlinna
authors: Multidisciplinary Breast Center, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
authors: Patrick
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authors: Neven
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Curtis
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authors: Olswold
authors: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors: Julian
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authors: Peto
authors: Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
authors: Dijana
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authors: Plaseska-Karanfilska
authors: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
authors: Katri
authors: K
authors: Pylkäs
authors: Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere, Scientifico, Istituto Nazionale Tumori, Milan, Italy.
authors: Paolo
authors: P
authors: Radice
authors: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors: Anja
authors: A
authors: Rudolph
authors: Research Oncology, Guy's Hospital, King's College London, London, UK.
authors: Elinor J
authors: EJ
authors: Sawyer
authors: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors: Marjanka K
authors: MK
authors: Schmidt
authors: Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Xiao-Ou
authors: XO
authors: Shu
authors: Department of Pathology, The University of Melbourne, Melbourne, Australia.
authors: Melissa C
authors: MC
authors: Southey
authors: Division of Genetics and Epidemiology & Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors: Anthony
authors: A
authors: Swerdlow
authors: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rob A E M
authors: RA
authors: Tollenaar
authors: Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
authors: Ian
authors: I
authors: Tomlinson
authors: Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.|Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
authors: Diana
authors: D
authors: Torres
authors: Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, VilleJuif, France.
authors: Thérèse
authors: T
authors: Truong
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Celine
authors: C
authors: Vachon
authors: Ans M W
authors: AM
authors: Van Den Ouweland
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Qin
authors: Q
authors: Wang
authors: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
authors: Robert
authors: R
authors: Winqvist
authors: Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Wei
authors: W
authors: Zheng
authors: Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.|Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
authors: Javier
authors: J
authors: Benitez
authors: Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Alison M
authors: AM
authors: Dunning
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Paul D P
authors: PD
authors: Pharoah
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors: Vessela
authors: V
authors: Kristensen
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Hall
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Douglas F
authors: DF
authors: Easton
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors: Tomi
authors: T
authors: Pastinen
authors: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors: Silje
authors: S
authors: Nord
authors: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada.
authors: Jacques
authors: J
authors: Simard
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002170:Canada; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4; D004265:DNA Helicases / Q000235:genetics; D005060:Europe; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D024101:Mitochondrial Proteins / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: C520310:ABRAXAS1 protein, human; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C000621827:MRPS18C protein, human; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C451406:HELQ protein, human
keywords: association studies; breast cancer; cis-regulatory variants; differential allelic expression; genetic susceptibility