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Eur J Hum Genet. 2017 Apr;25(4):432-438. doi: 10.1038/ejhg.2016.203. Epub 2017 Feb 1.

Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

Author information

Department of Pathology, University of Otago, Christchurch, New Zealand.
Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Biostatistics and Computational Biology Unit, Department of the Dean, University of Otago, Christchurch, New Zealand.
Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Department of Population Sciences Division of Clinical Cancer Genomics, City of Hope Clinical Cancer Genomics Community Research Network, Duarte, CA, USA.
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.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany.
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, Barcelona, Spain.
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
Department of Medicine, Cancer Biology and Genetics, Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA.
Department of Medicine and the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA.


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.

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