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

<div><p>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 <i>BRCA1</i> gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with <i>BRCA1</i> mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that <i>TP53</i> mutations and methylation of CpG dinucleotides in the <i>BRCA1</i> promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of <i>MYC</i>, <i>NOTCH2</i>, or <i>NOTCH3</i> and affected tumor suppressor genes including <i>RB1</i>, <i>PTEN</i>, and <i>KMT2C</i>. Furthermore, we identified putative <i>TGFA</i> enhancer regions. Recurrent SVs that affected the <i>TGFA</i> enhancer region led to enhanced expression of the <i>TGFA</i> 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.</p></div