Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1 Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. Although the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNA-seq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine-guided TNBC treatment.Significance: Using combined WES and RNA-seq analyses, we identified sporadic oncogenic events in TNBC mouse models that share the capacity to activate the MAPK and/or PI3K pathways. Our data support a treatment tailored to the genetics of individual tumors that parallels the approaches being investigated in the ongoing NCI-MATCH, My Pathway Trial, and ESMART clinical trials. Cancer Discov; 8(3); 354-69. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Matissek et al., p. 336This article is highlighted in the In This Issue feature, p. 253.

中文翻译：

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识别和靶向三阴性乳腺癌小鼠模型中的散发性致癌基因畸变。

三阴性乳腺癌 (TNBC) 的遗传特征是 TP53 畸变和常见致癌基因的低激活点突变率，这使得靶向治疗的应用具有挑战性。我们进行了全外显子组测序 (WES) 和 RNA 测序 (RNA-seq)，以鉴定 TNBC 小鼠模型中的体细胞遗传改变，这些改变是由 Trp53 单独缺失或与 Brca1 扩增或易位相结合导致癌蛋白表达升高或癌蛋白-在大约 50% 的评估肿瘤中发现分别含有融合基因和肿瘤抑制因子的移码突变。尽管零星遗传改变的范围多种多样，但大多数都具有激活 MAPK/PI3K 通路的共同能力。重要的，我们证明了批准的或实验性的药物可以有效地诱导肿瘤消退，特别是在含有药物靶标体细胞畸变的肿瘤中。我们的研究表明，WES 和 RNA-seq 在人类 TNBC 上的结合将导致确定可操作的治疗靶点，用于精准医学指导的 TNBC 治疗。意义：通过结合 WES 和 RNA-seq 分析，我们确定了 TNBC 中的散发性致癌事件具有激活 MAPK 和/或 PI3K 通路能力的小鼠模型。我们的数据支持针对个体肿瘤遗传学量身定制的治疗方法，该方法与正在进行的 NCI-MATCH、My Pathway 试验和 ESMART 临床试验中正在研究的方法相似。癌症发现；8(3); 354-69。©2017 AACR。参见 Natrajan 等人的相关评论，p. 272 参见 Matissek 等人的相关文章，p. 336这篇文章在本期专题中突出显示，p。253.