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Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the  BRCA1  gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with  BRCA1  mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that  TP53  mutations and methylation of CpG dinucleotides in the  BRCA1  promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of  MYC ,  NOTCH2 , or  NOTCH3  and affected tumor suppressor genes including  RB1 ,  PTEN , and  KMT2C . Furthermore, we identified putative  TGFA  enhancer regions. Recurrent SVs that affected the  TGFA  enhancer region led to enhanced expression of the  TGFA  oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications.

Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency