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人脑转移基因组特征揭示肺腺癌转移驱动基因
2020-03-29 23:35
来源：小柯机器人

近日，美国麻省总医院Priscilla K. Brastianos、丹娜-法伯癌症研究所Scott L. Carter等研究人员合作利用人类脑转移基因组特征鉴定出肺腺癌转移的驱动基因。这一研究成果于2020年3月23日在线发表在国际学术期刊《自然—遗传学》上。

为了确定促进脑转移的基因组改变，研究人员对73例肺腺癌脑转移（BM-LUAD）病例进行了全外显子测序。通过鉴定与503个原发性LUAD相比在BM-LUAD中具有更频繁的拷贝数畸变的基因，他们使用病例对照分析发现了脑转移的潜在驱动基因。研究人员在BM-LUAD中鉴定出三个扩增频率明显较高的区域，包括MYC（12% vs 6％）、YAP1（7% vs 0.8％）和MMP13（10% vs 0.6％），以及CDKN2A B的缺失频率更高（27% vs 13％）。研究人员证实，在105例BM-LUAD患者的独立队列中，MYC、YAP1和MMP13的扩增频率升高。在患者来源异种移植小鼠模型的功能评估证实了MYC、YAP1或MMP13过表达会增加脑转移发生率。这些结果表明，体细胞的改变有助于脑转移，而且足够数量的转移性肿瘤基因组测序可以揭示未知的转移驱动因子。
 
据介绍，BM-LUAD通常会导致患者死亡。
 
附：英文原文

Title: Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma

Author: David J. H. Shih, Naema Nayyar, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. DAndrea, Ugonma Chukwueke, Franziska Maria Ippen, Christopher Alvarez-Breckenridge, Nicholas D. Camarda, Matthew Lastrapes, Devin McCabe, Ben Kuter, Benjamin Kaufman, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Andrew Kaneb, Emily D. Batchelor, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A. John Iafrate, Bruce E. Johnson, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos

Issue&Volume: 2020-03-23

Abstract: 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.

DOI: 10.1038/s41588-020-0592-7

Source: https://www.nature.com/articles/s41588-020-0592-7

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex


本期文章：《自然—遗传学》：Online/在线发表

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