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Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

Glodzik, Dominik LU ; Bosch, Ana LU ; Hartman, Johan ; Aine, Mattias LU ; Vallon-Christersson, Johan LU orcid ; Reuterswärd, Christel LU ; Karlsson, Anna LU ; Mitra, Shamik LU ; Niméus, Emma LU and Holm, Karolina LU , et al. (2020) In Nature Communications 11(1).
Abstract
Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type,... (More)
Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
article number
3747
publisher
Nature Publishing Group
external identifiers
  • pmid:32719340
  • scopus:85088573653
  • pmid:32719340
ISSN
2041-1723
DOI
10.1038/s41467-020-17537-2
project
Sweden Cancerome Analysis Network - Breast (SCAN-B): a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine
language
English
LU publication?
yes
additional info
These authors contributed equally: Dominik Glodzik, Ana Bosch, Serena Nik-Zainal, Åke Borg, Johan Staaf.
id
04a4e502-d008-4fa8-a8bf-4e0a32ca41b2
date added to LUP
2020-07-28 10:24:44
date last changed
2024-02-16 19:31:05
@article{04a4e502-d008-4fa8-a8bf-4e0a32ca41b2,
  abstract     = {{Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.}},
  author       = {{Glodzik, Dominik and Bosch, Ana and Hartman, Johan and Aine, Mattias and Vallon-Christersson, Johan and Reuterswärd, Christel and Karlsson, Anna and Mitra, Shamik and Niméus, Emma and Holm, Karolina and Häkkinen, Jari and Hegardt, Cecilia and Saal, Lao H. and Larsson, Christer and Malmberg, Martin and Rydén, Lisa and Ehinger, Anna and Loman, Niklas and Kvist, Anders and Ehrencrona, Hans and Nik-zainal, Serena and Borg, Åke and Staaf, Johan}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-17537-2}},
  doi          = {{10.1038/s41467-020-17537-2}},
  volume       = {{11}},
  year         = {{2020}},
}