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


Authors: Glodzik, D.; Bosch, A.; Hartman, J.; Aine, M.; Vallon-Christersson, J.; Reuterswärd, C.; Karlsson, A.; Mitra, S.; Niméus, E.; Holm, K.; Häkkinen, J.; Hegardt, C.; Saal, L. H.; Larsson, C.; Malmberg, M.; Rydén, L.; Ehinger, A.; Loman, N.; Kvist, A.; Ehrencrona, H.; Nik-Zainal, S.; Borg, Å; Staaf, J.
Article Title: Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
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. © 2020, The Author(s).
Keywords: methylation; mutation; chemotherapy; phenotype; protein; blood; dna; biomarker; molecular analysis; genome; tumor; recombination; infiltration; cancer
Journal Title: Nature Communications
Volume: 11
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2020-07-27
Start Page: 3747
Language: English
DOI: 10.1038/s41467-020-17537-2
PUBMED: 32719340
PROVIDER: scopus
PMCID: PMC7385112
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Dominik Glodzik
    16 Glodzik