Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
Dominik Głodzik, Ana Bosch, Johan Hartman, Mattias Aine, Johan Vallon‐Christersson, Christel Reuterswärd, Anna Karlsson, Shamik Mitra, Emma Niméus, Karolina Holm, Jari Häkkinen, Cecilia Hegardt, Lao H. Saal, Christer Larsson, Martin Malmberg, Lisa Rydén, Anna Ehinger, Niklas Loman, Anders Kvist, Hans Ehrencrona, Serena Nik‐Zainal, Åke Borg, Johan Staaf
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.