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

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Glodzik, Dominik 
Bosch, Ana 
Vallon-Christersson, Johan 


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.


Funder: The Governmental Funding for Young Clinical Researchers within the National Health Service (ALF) 2017-2019

Funder: Shamik Mitra is financially supported by the funding received from the European Community’s Horizon 2020 Framework Program for Research and Innovation (H2020-MSCA-ITN-2014) under Grant Agreement no. 247634

Funder: Vetenskapsrådet (Swedish Research Council); doi:

Funder: The Governmental Funding within the National Health Service (ALF)

Funder: - The Governmental Funding of Clinical Research within the National Health Service (ALF), grant nbr 2018/40612 - The Gustav V:s Jubilee Foundation (174271 and 187041) - The research foundation at Department of Oncology in Lund


Article, /631/67/69, /692/53/2422, /692/4028/67/1347, /38, /38/91, /38/39, /45/23, /49/23, /49/61, article

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Nature Communications

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Nature Publishing Group UK
Fru Berta Kamprads Stiftelse (Mrs. Berta Kamprad Foundation) (FBKS 2017-34-199, FBKS-2018-4-146)
Gunnar Nilssons Cancerstiftelse (Gunnar Nilsson Cancer Foundation) (GN-2018-5)
Cancerfonden (Swedish Cancer Society) (CAN 2018/685)
Crafoordska Stiftelsen (Crafoord Foundation) (20180543)