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The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.

Jönsson, Göran B LU ; Staaf, Johan LU ; Vallon-Christersson, Johan LU ; Ringnér, Markus LU ; Gruvberger, Sofia LU ; Saal, Lao LU ; Holm, Karolina LU ; Hegardt, Cecilia LU ; Arason, Adalgeir and Fagerholm, Rainer, et al. (2012) In Cancer Research 72(16). p.4028-4036
Abstract
Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was... (More)
Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status. (Less)
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Contribution to journal
publication status
published
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Cancer Research
volume
72
issue
16
pages
4028 - 4036
publisher
American Association for Cancer Research
external identifiers
  • WOS:000307881100016
  • PMID:22706203
  • Scopus:84865146340
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-12-0097
project
CREATE Health
language
English
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yes
id
dce0c9b8-8fc3-418b-b2f9-4638b38962dd (old id 2859279)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22706203?dopt=Abstract
date added to LUP
2012-07-04 18:01:48
date last changed
2016-12-08 10:22:14
@misc{dce0c9b8-8fc3-418b-b2f9-4638b38962dd,
  abstract     = {Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status.},
  author       = {Jönsson, Göran B and Staaf, Johan and Vallon-Christersson, Johan and Ringnér, Markus and Gruvberger, Sofia and Saal, Lao and Holm, Karolina and Hegardt, Cecilia and Arason, Adalgeir and Fagerholm, Rainer and Olsson, Camilla and Grabau, Dorthe and Johnsson, Ellinor and Lövgren, Kristina and Magnusson, Linda and Heikkilä, Paivi and Agnarsson, Bjarni A and Johannsson, Oskar Th and Malmström, Per and Fernö, Mårten and Olsson, Håkan and Loman, Niklas and Nevanlinna, Heli and Barkardottir, Rosa Bjork and Borg, Åke},
  issn         = {1538-7445},
  language     = {eng},
  number       = {16},
  pages        = {4028--4036},
  publisher    = {ARRAY(0x9b14fb0)},
  series       = {Cancer Research},
  title        = {The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-12-0097},
  volume       = {72},
  year         = {2012},
}