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- Title
Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers.
- Authors
Glodzik, Dominik; Bosch, Ana; Hartman, Johan; Aine, Mattias; Vallon-Christersson, Johan; Reuterswärd, Christel; Karlsson, Anna; Mitra, Shamik; Niméus, Emma; Holm, Karolina; Häkkinen, Jari; Hegardt, Cecilia; Saal, Lao H.; Larsson, Christer; Malmberg, Martin; Rydén, Lisa; Ehinger, Anna; Loman, Niklas; Kvist, Anders; Ehrencrona, Hans
- 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. BRCA-deficient breast cancer is characterised by homologous recombination deficiency. Here, the authors show that hypermethylated BRCA1 phenotypically copies mutated BRCA1 in triple negative breast cancers.
- Subjects
TRIPLE-negative breast cancer; BRCA genes; EPIGENOMICS; BIOMARKERS
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-17537-2