title: Genome instability in blood cells of a BRCA1+ breast cancer family.
abstract: BACKGROUND
  BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability.
  
  
  METHODS
  Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members.
  
  
  RESULTS
  We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo.
  
  
  CONCLUSIONS
  Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Xiao
authors.forename: Yeong C
authors.initials: YC
authors.lastname: Kim
authors.forename: Carrie
authors.initials: C
authors.lastname: Snyder
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Wen
authors.forename: Pei Xian
authors.initials: PX
authors.lastname: Chen
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Luo
authors.forename: Dina
authors.initials: D
authors.lastname: Becirovic
authors.forename: Bradley
authors.initials: B
authors.lastname: Downs
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Cowan
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, Omaha, NE 68198, USA. htlynch@creighton.edu.
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: San Ming
authors.initials: SM
authors.lastname: Wang
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000097:blood / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D040941:Heredity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009035:Mothers; D009154:Mutation; D009679:Nuclear Family; D010375:Pedigree; D010641:Phenotype
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor