Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Nat Genet. 2020 Apr;52(4):371-377. doi: 10.1038/s41588-020-0592-7. Epub 2020 Mar 23.
Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
肺腺癌脑转移（BM-LUAD）常导致患者死亡。为了确定促进脑转移的基因组改变，我们对 73 例 BM-LUAD 病例进行了全外显子组测序。通过比较 BM-LUAD 与 503 例原发性 LUAD 中更频繁的拷贝数异常，我们采用病例对照分析，发现了脑转移的候选驱动基因。我们在 BM-LUAD 中发现了三个区域的扩增频率明显升高，包括 MYC（12%对 6%）、YAP1（7%对 0.8%）和 MMP13（10%对 0.6%），CDKN2A/B 的缺失频率也明显更高（27%对 13%）。我们在 105 例 BM-LUAD 患者的独立队列中证实了 MYC、YAP1 和 MMP13 的扩增频率升高。在患者来源的异种移植小鼠模型中的功能评估验证了 MYC、YAP1 或 MMP13 过表达增加脑转移发生率的观点。这些结果表明，体细胞改变有助于脑转移，对足够数量的转移性肿瘤进行基因组测序可以揭示以前未知的转移性驱动因素。
