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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Saal, Lao LU ; Gruvberger, Sofia LU ; Persson, Camilla LU ; Lövgren, Kristina LU ; Staaf, Johan LU ; Jönsson, Göran B LU ; Pires, MM; Holm, Karolina LU ; Vallon-Christersson, Johan LU and Olsson, Håkan LU , et al. (2008) In Nature Genetics 40(1). p.102-107
Abstract
Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1, 2, 3. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype3, 4, 5; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic... (More)
Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1, 2, 3. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype3, 4, 5; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair. (Less)
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published
subject
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Nature Genetics
volume
40
issue
1
pages
102 - 107
publisher
Nature Publishing Group
external identifiers
  • wos:000252118600025
  • scopus:37549020704
ISSN
1546-1718
DOI
10.1038/ng.2007.39
project
CREATE Health
language
English
LU publication?
yes
id
cda89a07-bdb4-4428-86a0-0f0e2aabd064 (old id 801721)
date added to LUP
2007-12-28 16:02:27
date last changed
2017-09-03 04:54:16
@article{cda89a07-bdb4-4428-86a0-0f0e2aabd064,
  abstract     = {Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1, 2, 3. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype3, 4, 5; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair.},
  author       = {Saal, Lao and Gruvberger, Sofia and Persson, Camilla and Lövgren, Kristina and Staaf, Johan and Jönsson, Göran B and Pires, MM and Holm, Karolina and Vallon-Christersson, Johan and Olsson, Håkan and Krogh, Morten and Isola, Jorma and Borg, Åke},
  issn         = {1546-1718},
  language     = {eng},
  number       = {1},
  pages        = {102--107},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair},
  url          = {http://dx.doi.org/10.1038/ng.2007.39},
  volume       = {40},
  year         = {2008},
}