Zheng Siyuan, Cherniack Andrew D, Dewal Ninad, Moffitt Richard A, Danilova Ludmila, Murray Bradley A, Lerario Antonio M, Else Tobias, Knijnenburg Theo A, Ciriello Giovanni, Kim Seungchan, Assie Guillaume, Morozova Olena, Akbani Rehan, Shih Juliann, Hoadley Katherine A, Choueiri Toni K, Waldmann Jens, Mete Ozgur, Robertson A Gordon, Wu Hsin-Ta, Raphael Benjamin J, Shao Lina, Meyerson Matthew, Demeure Michael J, Beuschlein Felix, Gill Anthony J, Sidhu Stan B, Almeida Madson Q, Fragoso Maria C B V, Cope Leslie M, Kebebew Electron, Habra Mouhammed A, Whitsett Timothy G, Bussey Kimberly J, Rainey William E, Asa Sylvia L, Bertherat Jérôme, Fassnacht Martin, Wheeler David A, Hammer Gary D, Giordano Thomas J, Verhaak Roel G W
Departments of Genomic Medicine, Bioinformatics, and Computational Biology, Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Cancer Cell. 2016 May 9;29(5):723-736. doi: 10.1016/j.ccell.2016.04.002.
We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.
我们描述了肾上腺皮质癌(ACC)的全面基因组特征。利用该数据集,我们扩充了已知的ACC驱动基因目录,纳入了PRKAR1A、RPL22、TERF2、CCNE1和NF1。全基因组DNA拷贝数分析显示,频繁出现大量DNA缺失,随后发生全基因组加倍(WGD),这与侵袭性临床病程相关,提示WGD是疾病进展的一个标志。TERT表达增加、端粒长度缩短以及细胞周期程序激活均证实了这一假说。综合亚型分析确定了三种ACC亚型,它们具有不同的临床结局和分子改变,可通过一个68-CpG探针DNA甲基化特征来捕获,从而提出了一种基于分子标志物对患者进行临床分层的策略。