title: Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.
abstract: BACKGROUND
  Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown.
  
  
  METHODS
  We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease. We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes.
  
  
  RESULTS
  We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes (TP53, PALB2, ATM, CHEK2, CDH1, PTEN and STK11) in 45 cases, and 22 potential deleterious mutations in 31 cases in 8 other genes (BARD1, BRIP1, MRE11, NBN, RAD50, RAD51C, RAD51D and CDK4). The relevant variants were then genotyped in 558 family members. Assuming a constant relative risk of breast cancer across age groups, only variants in CDH1, CHEK2, PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk.
  
  
  CONCLUSIONS
  Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes, but very large case-control sequencing studies and/or larger family-based studies will be needed to define the risks more accurately.
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: Huong
authors.initials: H
authors.lastname: Meeks
authors.affiliation: Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.affiliation: kConFab, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Igor
authors.initials: I
authors.lastname: Makunin
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ellis
authors.affiliation: kConFab, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Campbell
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Southey
authors.affiliation: The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Tissupath, Mount Waverley, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Clouston
authors.affiliation: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia Westmead Hospital, Sydney, Australia.
authors.forename: Judy
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D005091:Exons; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree
chemical_list: D014408:Biomarkers, Tumor
keywords: Cancer: breast