title: Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes.
abstract: BACKGROUND
  Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.
  
  
  METHODS
  We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.
  
  
  RESULTS
  First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.
  
  
  CONCLUSIONS
  This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.
authors.affiliation: Bioinformatics and Biostatistics Unit, and Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain. nbonifaci@iconcologia.net
authors.forename: Núria
authors.initials: N
authors.lastname: Bonifaci
authors.forename: Antoni
authors.initials: A
authors.lastname: Berenguer
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: Oscar
authors.initials: O
authors.lastname: Reina
authors.forename: Ignacio
authors.initials: I
authors.lastname: Medina
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pujana