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Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency.

Rennstam, Karin LU ; Ringberg, Anita LU ; Cunliffe, Heather E; Olsson, Håkan LU ; Landberg, Göran LU and Hedenfalk, Ingrid LU (2010) In Genes, Chromosomes and Cancer 49. p.78-90
Abstract
Multiple biopsies of normal breast tissue from 10 BRCA1 mutation carriers have been analyzed using array-based comparative genomic hybridization. Normal breast tissue from five age-matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from BRCA1 mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of... (More)
Multiple biopsies of normal breast tissue from 10 BRCA1 mutation carriers have been analyzed using array-based comparative genomic hybridization. Normal breast tissue from five age-matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from BRCA1 mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of tissue heterogeneity and etiological clonality in the breast epithelium. We show that neither loss of heterozygosity nor promoter methylation of the wild-type BRCA1 allele is the predominant mechanistic origin of the observed genomic instability. Instead, we propose that haploinsufficiency of BRCA1 might be the underlying cause responsible for initiation of breast cancer in these predisposed women, making cells vulnerable to mitotic recombination. We also propose that loss of ERalpha expression is preceded by genetic instability in the initiation of BRCA1-dependent tumorigenesis, indicating that the breast epithelium of BRCA1 mutation carriers may initially be estrogen-responsive. Our results imply that genomic instability instigated by BRCA1 haploinsufficiency may be required for breast cancer initiation in BRCA1 mutation carriers. Finding molecular markers of tumor initiation and progression, for the potential use in early disease detection, may be of great clinical importance for the improved management of at-risk women. (c) 2009 Wiley-Liss, Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genes, Chromosomes and Cancer
volume
49
pages
78 - 90
publisher
John Wiley & Sons
external identifiers
  • wos:000272214800009
  • pmid:19839046
  • scopus:74949104849
ISSN
1045-2257
DOI
10.1002/gcc.20723
language
English
LU publication?
yes
id
5876f03c-3f01-43b2-b8a4-3c136ff2ce8e (old id 1500227)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19839046?dopt=Abstract
date added to LUP
2009-11-03 13:46:42
date last changed
2018-05-29 09:54:28
@article{5876f03c-3f01-43b2-b8a4-3c136ff2ce8e,
  abstract     = {Multiple biopsies of normal breast tissue from 10 BRCA1 mutation carriers have been analyzed using array-based comparative genomic hybridization. Normal breast tissue from five age-matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from BRCA1 mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of tissue heterogeneity and etiological clonality in the breast epithelium. We show that neither loss of heterozygosity nor promoter methylation of the wild-type BRCA1 allele is the predominant mechanistic origin of the observed genomic instability. Instead, we propose that haploinsufficiency of BRCA1 might be the underlying cause responsible for initiation of breast cancer in these predisposed women, making cells vulnerable to mitotic recombination. We also propose that loss of ERalpha expression is preceded by genetic instability in the initiation of BRCA1-dependent tumorigenesis, indicating that the breast epithelium of BRCA1 mutation carriers may initially be estrogen-responsive. Our results imply that genomic instability instigated by BRCA1 haploinsufficiency may be required for breast cancer initiation in BRCA1 mutation carriers. Finding molecular markers of tumor initiation and progression, for the potential use in early disease detection, may be of great clinical importance for the improved management of at-risk women. (c) 2009 Wiley-Liss, Inc.},
  author       = {Rennstam, Karin and Ringberg, Anita and Cunliffe, Heather E and Olsson, Håkan and Landberg, Göran and Hedenfalk, Ingrid},
  issn         = {1045-2257},
  language     = {eng},
  pages        = {78--90},
  publisher    = {John Wiley & Sons},
  series       = {Genes, Chromosomes and Cancer},
  title        = {Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency.},
  url          = {http://dx.doi.org/10.1002/gcc.20723},
  volume       = {49},
  year         = {2010},
}