title: The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance.
abstract: More than 12 % of women will be diagnosed with breast cancer in their lifetime. Although there have been tremendous advances in elucidating genetic risk factors underlying both familial and sporadic breast cancer, much of the genetic contribution to breast cancer etiology remains unknown. The discovery of BRCA1 and BRCA2 over 20 years ago remains the seminal event in the field and has paved the way for the discovery of other high-penetrance susceptibility genes by linkage analysis. The advent of genome-wide association studies made possible the next wave of discoveries, in which over 80 low-penetrance and moderate-penetrance variants were identified. Although these studies were highly successful at discovering variants associated with both familial and sporadic breast cancer, the variants identified to date explain only 50 % of the heritability of breast cancer. In this review, we look back at the investigative strategies that have led to our current understanding of breast cancer genetics, consider the challenges of performing association studies in heterogeneous complex diseases such as breast cancer, and look ahead toward the types of study designs that may lead to the identification of the genetic variation accounting for the remaining missing heritability.
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Skol
authors.affiliation: Department of Biology, Hamilton College, Clinton, NY, 13323, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Sasaki
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, IL, 60637, USA. konel@northwell.edu.|Section of Hematology/Oncology, Department of Pediatrics, The University of Chicago, KCBD 5140, 900 East 57th Street, Chicago, IL, 60637, USA. konel@northwell.edu.
authors.forename: Kenan
authors.identifier: 0000-0002-2021-6250
authors.initials: K
authors.lastname: Onel
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D004777:Environment; D005190:Family; D005260:Female; D059647:Gene-Environment Interaction; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019683:Penetrance; D018570:Risk Assessment
keywords: Genetics; Genome-wide association study; Genomics; Linkage analysis; Next-generation sequencing; Penetrance; Predisposition