人腦轉(zhuǎn)移基因組特征揭示肺腺癌轉(zhuǎn)移驅(qū)動基因
近日，美國麻省總醫(yī)院Priscilla K. Brastianos、丹娜-法伯癌癥研究所Scott L. Carter等研究人員合作利用人類腦轉(zhuǎn)移基因組特征鑒定出肺腺癌轉(zhuǎn)移的驅(qū)動基因。這一研究成果于2020年3月23日在線發(fā)表在國際學(xué)術(shù)期刊《自然—遺傳學(xué)》上。
為了確定促進腦轉(zhuǎn)移的基因組改變，研究人員對73例肺腺癌腦轉(zhuǎn)移（BM-LUAD）病例進行了全外顯子測序。通過鑒定與503個原發(fā)性LUAD相比在BM-LUAD中具有更頻繁的拷貝數(shù)畸變的基因，他們使用病例對照分析發(fā)現(xiàn)了腦轉(zhuǎn)移的潛在驅(qū)動基因。研究人員在BM-LUAD中鑒定出三個擴增頻率明顯較高的區(qū)域，包括MYC（12% vs 6％）、YAP1（7% vs 0.8％）和MMP13（10% vs 0.6％），以及CDKN2A B的缺失頻率更高（27% vs 13％）。研究人員證實，在105例BM-LUAD患者的獨立隊列中，MYC、YAP1和MMP13的擴增頻率升高。在患者來源異種移植小鼠模型的功能評估證實了MYC、YAP1或MMP13過表達會增加腦轉(zhuǎn)移發(fā)生率。這些結(jié)果表明，體細胞的改變有助于腦轉(zhuǎn)移，而且足夠數(shù)量的轉(zhuǎn)移性腫瘤基因組測序可以揭示未知的轉(zhuǎn)移驅(qū)動因子。
據(jù)介紹，BM-LUAD通常會導(dǎo)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
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