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

• Published in: Nature communications Vol. 11; no. 1; p. 3747
• Main 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, Nik-Zainal, Serena, Borg, Åke, Staaf, Johan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/39; 38/91; 45/23; 49/23; 49/61; 631/67/69; 692/4028/67/1347; 692/53/2422; Adult; Aged; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Basic Medicine; Biomarkers; BRCA1 protein; BRCA1 Protein - deficiency; BRCA1 Protein - genetics; Breast cancer; Cancer and Oncology; Cancer och onkologi; Chemotherapy; Clinical Medicine; Cohort Studies; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Epigenetics; Female; Gene Expression Regulation, Neoplastic; Gene frequency; Gene sequencing; Genetic analysis; Genomes; Homologous recombination; Homology; Humanities and Social Sciences; Humans; Immune system; Klinisk medicin; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Metastases; Middle Aged; multidisciplinary; Mutation - genetics; Peripheral blood; Phenotype; Phenotypes; Population studies; Prognosis; Promoter Regions, Genetic; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Transcription, Genetic; Transcriptomics; Treatment Outcome; Triple Negative Breast Neoplasms - blood; Triple Negative Breast Neoplasms - diagnosis; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - therapy; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17537-2

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.