Whole-exome sequencing of Finnish hereditary breast cancer families

Eur J Hum Genet. 2016 Jan;25(1):85-93. doi: 10.1038/ejhg.2016.141. Epub 2016 Oct 26.


A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms / genetics*
  • Cell Cycle Proteins / genetics
  • DNA Repair / genetics
  • Exome / genetics*
  • Exonucleases / genetics
  • Female
  • Finland
  • Genetic Predisposition to Disease*
  • Genotype
  • Germ-Line Mutation / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Pedigree
  • Proto-Oncogene Proteins c-myc / genetics
  • Ribonucleotide Reductases / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • Cell Cycle Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RRM2B protein, human
  • Ribonucleotide Reductases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Exonucleases
  • Rad1 protein, human

Supplementary concepts

  • Breast Cancer, Familial