Kawazu Masahito, Kojima Shinya, Ueno Toshihide, Totoki Yasushi, Nakamura Hiromi, Kunita Akiko, Qu Wei, Yoshimura Jun, Soda Manabu, Yasuda Takahiko, Hama Natsuko, Saito-Adachi Mihoko, Sato Kazuhito, Kohsaka Shinji, Sai Eirin, Ikemura Masako, Yamamoto Shigeru, Ogawa Tomoko, Fukayama Masashi, Tada Keiichiro, Seto Yasuyuki, Morishita Shinichi, Hazama Shoichi, Shibata Tatsuhiro, Yamashita Yoshihiro, Mano Hiroyuki
Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
PLoS Genet. 2017 Jun 21;13(6):e1006853. doi: 10.1371/journal.pgen.1006853. eCollection 2017 Jun.
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.
三阴性乳腺癌（TNBC）细胞不表达雌激素受体、孕激素受体或人表皮生长因子受体2。目前，除了聚ADP核糖聚合酶抑制剂外，针对这类癌症几乎没有有效的治疗选择。在此，我们展示了通过高覆盖度全基因组测序以及转录组和全外显子测序对TNBC中的基因改变进行的全面表征。BRCA1基因的沉默在一部分TNBC中损害了同源重组途径，这些TNBC表现出与具有BRCA1突变的肿瘤相似的表型；它们含有许多结构变异（SVs），其中串联重复相对富集。克隆分析表明，TP53突变和BRCA1启动子中CpG二核苷酸的甲基化是致癌作用的早期事件。SVs与驱动致癌事件相关，如MYC、NOTCH2或NOTCH3的扩增，并影响包括RB1、PTEN和KMT2C在内的肿瘤抑制基因。此外，我们鉴定出了假定的TGFA增强子区域。影响TGFA增强子区域的复发性SVs导致编码表皮生长因子受体高亲和力配体之一的TGFA癌基因表达增强。我们还鉴定出了多种可转化3T3小鼠成纤维细胞的癌基因，这表明单个TNBC肿瘤可能经历了可靶向的独特驱动事件。因此，我们揭示了TNBC的几个具有临床重要意义的特征。
