title: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.
abstract: Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Logan C
authors.initials: LC
authors.lastname: Walker
authors.affiliation: Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.affiliation: Biostatistics and Computational Biology Unit, Department of the Dean, University of Otago, Christchurch, New Zealand.
authors.forename: John F
authors.initials: JF
authors.lastname: Pearson
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: George A R
authors.initials: GA
authors.lastname: Wiggins
authors.affiliation: Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: O'Mara
authors.affiliation: Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Parsons
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Barrowdale
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
authors.forename: Lesley
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authors.lastname: McGuffog
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Javier
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authors.lastname: Benitez
authors.affiliation: Department of Population Sciences Division of Clinical Cancer Genomics, City of Hope Clinical Cancer Genomics Community Research Network, Duarte, CA, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Slavin
authors.affiliation: Department of Preventive and Predictive Medicine, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Frost
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.affiliation: Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany.
authors.forename: Rita Katharina
authors.initials: RK
authors.lastname: Schmutzler
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Beth N
authors.initials: BN
authors.lastname: Peshkin
authors.affiliation: Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
authors.forename: Trinidad
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authors.lastname: Caldes
authors.affiliation: Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Frans Bl
authors.initials: FB
authors.lastname: Hogervorst
authors.affiliation: Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, Barcelona, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lazaro
authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.affiliation: Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicine, Cancer Biology and Genetics, Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hulick
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.affiliation: Department of Medicine and the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Katherine L
authors.identifier: 0000-0002-6740-0901
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.affiliation: Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D000072467:Cytochrome P450 Family 2 / Q000235:genetics; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D060045:Genes, Modifier; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D011268:Pregnancy-Specific beta 1-Glycoproteins / Q000235:genetics; D019473:Transcription Factors, TFII / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C000597036:NAALADL2 protein, human; C418982:PSG5 protein, human; D011268:Pregnancy-Specific beta 1-Glycoproteins; D019473:Transcription Factors, TFII; C494418:ZNF385A protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C423964:CYP2A7 protein, human; D000072467:Cytochrome P450 Family 2; D043425:Glutamate Carboxypeptidase II