copy number variation analysis in familial BRCA1/2-negative Finnish breast and ovarian cancer

PLoS One. 2013 Aug 13;8(8):e71802. doi: 10.1371/journal.pone.0071802. eCollection 2013.


Background: Inherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population.

Methods: A cohort of 84 HBOC individuals (negative for BRCA1/2-founder mutations and pre-screened for the most common breast cancer genes) and 36 healthy controls were analysed with a genome-wide SNP array. CNV-affecting genes were further studied by Gene Ontology term enrichment, pathway analyses, and database searches to reveal genes with potential for breast and ovarian cancer predisposition. CNVs that were considered to be important were validated and genotyped in 20 additional HBOC individuals (6 CNVs) and in additional healthy controls (5 CNVs) by qPCR.

Results: An intronic deletion in the EPHA3 receptor tyrosine kinase was enriched in HBOC individuals (12 of 101, 11.9%) compared with controls (27 of 432, 6.3%) (OR = 1.96; P = 0.055). EPHA3 was identified in several enriched molecular functions including receptor activity. Both a novel intronic deletion in the CSMD1 tumor suppressor gene and a homozygous intergenic deletion at 5q15 were identified in 1 of 101 (1.0%) HBOC individuals but were very rare (1 of 436, 0.2% and 1 of 899, 0.1%, respectively) in healthy controls suggesting that these variants confer disease susceptibility.

Conclusion: This study reveals new information regarding the germline CNVs that likely contribute to HBOC susceptibility in Finland. This information may be used to facilitate the genetic counselling of HBOC individuals but the preliminary results warrant additional studies of a larger study group.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • DNA Copy Number Variations*
  • Female
  • Finland
  • Gene Deletion
  • Gene Duplication
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Germ-Line Mutation
  • Hereditary Breast and Ovarian Cancer Syndrome / genetics*
  • Hereditary Breast and Ovarian Cancer Syndrome / pathology
  • Humans
  • Middle Aged
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Reproducibility of Results
  • Whites / genetics*
  • Young Adult

Grant support

This research was funded in part by the Academy of Finland (grant 251074) and the Competitive Research Funding of the Tampere University Hospital (grant 9M094). The Finnish Cultural Foundation has supported author KMK as well. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.