title: Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles.
abstract: The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.
authors: Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors: Francisco Javier
authors: FJ
authors: Gracia-Aznarez
authors: Victoria
authors: V
authors: Fernandez
authors: Guillermo
authors: G
authors: Pita
authors: Paolo
authors: P
authors: Peterlongo
authors: Orlando
authors: O
authors: Dominguez
authors: Miguel
authors: M
authors: de la Hoya
authors: Mercedes
authors: M
authors: Duran
authors: Ana
authors: A
authors: Osorio
authors: Leticia
authors: L
authors: Moreno
authors: Anna
authors: A
authors: Gonzalez-Neira
authors: Juan Manuel
authors: JM
authors: Rosa-Rosa
authors: Olga
authors: O
authors: Sinilnikova
authors: Sylvie
authors: S
authors: Mazoyer
authors: John
authors: J
authors: Hopper
authors: Conchi
authors: C
authors: Lazaro
authors: Melissa
authors: M
authors: Southey
authors: Fabrice
authors: F
authors: Odefrey
authors: Siranoush
authors: S
authors: Manoukian
authors: Irene
authors: I
authors: Catucci
authors: Trinidad
authors: T
authors: Caldes
authors: Henry T
authors: HT
authors: Lynch
authors: Florentine S M
authors: FS
authors: Hilbers
authors: Christi J
authors: CJ
authors: van Asperen
authors: Hans F A
authors: HF
authors: Vasen
authors: David
authors: D
authors: Goldgar
authors: Paolo
authors: P
authors: Radice
authors: Peter
authors: P
authors: Devilee
authors: Javier
authors: J
authors: Benitez
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D059472:Exome; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans