Extensive epigenomic dysregulation is a hallmark of homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with substantial disease heterogeneity, limited treatment options, and dismal clinical outcomes. Some TNBCs display homologous recombination deficiency (HRD), a phenotype with elevated genomic burden and worse prognosis if left untreated but chemotherapeutic sensitivity. While the molecular landscape of TNBC is distinct from other breast cancer subtypes, the TNBC-specific link between HRD and epigenome-wide methylation has not been established. This study reports two independent cohorts of TNBC tumors (n = 32 and n = 58) with HRD and epigenomic landscapes measured by the Multiplex Ligation-dependent Probe Amplification assay and the Illumina MethylationEPIC arrays, respectively. Genome-wide copy number and methylation alterations were significantly higher in HRD (all p <.05). Methylation of genome-wide repeat element Alu and transcriptional regulatory regions were significantly lower in HRD (all p <.05). An age-adjusted epigenome-wide association study of the continuous HRD probability scores revealed significant loci (all FDR <0.05) that were depleted from the CpG-rich "island" regions often seen in gene promoters but enriched in the CpG-poor "open sea" regions localized to gene enhancers. The significant loci implicated well-known candidate genes involved in the epithelial-to-mesenchymal transition, Wnt signaling, and DNA damage response. Supervised machine learning of HRD with nucleotide-specific methylation as the input enabled clinically relevant tumor stratification. Taken together, this study provides novel biological and translational insights into HRD in TNBCs.