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Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer

Kuusisto, Kirsi M. ; Akinrinade, Oyediran ; Vihinen, Mauno LU ; Kankuri-Tammilehto, Minna ; Laasanen, Satu-Leena and Schleutker, Johanna (2013) In PLoS ONE 8(8).
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... (More)
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. (Less)
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Contribution to journal
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published
subject
in
PLoS ONE
volume
8
issue
8
article number
e71802
publisher
Public Library of Science
external identifiers
  • wos:000323115800083
  • scopus:84881515732
  • pmid:23967248
ISSN
1932-6203
DOI
10.1371/journal.pone.0071802
language
English
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yes
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9bf2c328-13e3-4187-8715-35b3140df15a (old id 4025880)
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2016-04-01 15:00:47
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2020-01-12 18:01:09
@article{9bf2c328-13e3-4187-8715-35b3140df15a,
  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.},
  author       = {Kuusisto, Kirsi M. and Akinrinade, Oyediran and Vihinen, Mauno and Kankuri-Tammilehto, Minna and Laasanen, Satu-Leena and Schleutker, Johanna},
  issn         = {1932-6203},
  language     = {eng},
  number       = {8},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer},
  url          = {https://lup.lub.lu.se/search/ws/files/4297359/4349426.pdf},
  doi          = {10.1371/journal.pone.0071802},
  volume       = {8},
  year         = {2013},
}