A1 Refereed original research article in a scientific journal
Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer
Authors: Kirsi M Kuusisto, Oyediran Akinrinade, Mauno Vihinen, Minna Kankuri-Tammilehto, Satu-Leena Laasanen, Johanna Schleutker
Publication year: 2013
Journal: PLoS ONE
Article number: e71802
Number in series: 8
Volume: 8
Issue: 8
Number of pages: 8
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0071802
Abstract
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.
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.
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