Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.,Nature Genetics

当前位置： X-MOL 学术 › Nat. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-03-23 , DOI: 10.1038/s41588-020-0592-7
David J H Shih _{1,

2,

3} , Naema Nayyar _{3,

4,

5,

6} , Ivanna Bihun _{3,

5,

6} , Ibiayi Dagogo-Jack ₅ , Corey M Gill _{5,

6,

7} , Elisa Aquilanti _{3,

5,

8} , Mia Bertalan _{5,

6} , Alexander Kaplan _{5,

6} , Megan R D'Andrea _{5,

6} , Ugonma Chukwueke ₈ , Franziska Maria Ippen _{5,

6} , Christopher Alvarez-Breckenridge ₉ , Nicholas D Camarda _{2,

8,

10} , Matthew Lastrapes _{1,

2,

3,

5,

8} , Devin McCabe _{2,

3,

8} , Ben Kuter _{5,

6} , Benjamin Kaufman _{3,

8,

10} , Matthew R Strickland _{5,

6,

8} , Juan Carlos Martinez-Gutierrez _{5,

6,

11} , Deepika Nagabhushan _{5,

6} , Magali De Sauvage _{5,

6} , Michael D White _{5,

6} , Brandyn A Castro _{5,

6} , Kaitlin Hoang _{5,

6} , Andrew Kaneb _{5,

6} , Emily D Batchelor _{5,

6} , Sun Ha Paek _{12,

13} , Sun Hye Park _{12,

13} , Maria Martinez-Lage ₁₄ , Anna S Berghoff ₁₅ , Parker Merrill ₁₆ , Elizabeth R Gerstner ₆ , Tracy T Batchelor ₆ , Matthew P Frosch ₁₄ , Ryan P Frazier ₁₄ , Darrell R Borger ₁₄ , A John Iafrate ₁₄ , Bruce E Johnson _{8,

10} , Sandro Santagata _{16,

17,

18} , Matthias Preusser ₁₅ , Daniel P Cahill ₉ , Scott L Carter _{1,

2,

3,

8,

10} , Priscilla K Brastianos _{3,

5,

6}

Affiliation

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.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Program in Molecular Medicine, UMass Medical School, Worcester, MA, USA.
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Icahn School of Medicine, Mount Sinai, New York, NY, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Department of Neurosurgery, Seoul National University College of Medicine, Seoul, South Korea.
Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Department of Medicine I, Division of Oncology, Medical University of Vienna, Comprehensive Cancer Center Vienna, Vienna, Austria.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard Medical School, Boston, MA, USA.

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.

中文翻译：

人脑转移的基因组特征确定了转移性肺腺癌的驱动因素。

肺腺癌脑转移 (BM-LUAD) 经常导致患者死亡。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。通过病例对照分析，我们通过识别 BM-LUAD 中与 503 个原发 LUAD 相比具有更频繁拷贝数畸变的基因，发现了脑转移的候选驱动因素。我们确定了 BM-LUAD 中扩增频率显着较高的三个区域，包括 MYC（12% 对 6%）、YAP1（7% 对 0.8%）和 MMP13（10% 对 0.6%），并且 CDKN2A/B 中的缺失频率明显更高（27相对于 13%）。我们证实，在由 105 名 BM-LUAD 患者组成的独立队列中，MYC、YAP1 和 MMP13 的扩增频率升高。患者来源的异种移植小鼠模型的功能评估验证了 MYC、YAP1 或 MMP13 过度表达会增加脑转移发生率的观点。这些结果表明，体细胞改变导致脑转移，并且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驱动因素。

更新日期：2020-04-24

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11