Pugh T J, Yu W, Yang J, Field A L, Ambrogio L, Carter S L, Cibulskis K, Giannikopoulos P, Kiezun A, Kim J, McKenna A, Nickerson E, Getz G, Hoffher S, Messinger Y H, Dehner L P, Roberts C W M, Rodriguez-Galindo C, Williams G M, Rossi C T, Meyerson M, Hill D A
1] Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Dana-Farber Cancer Institute, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA.
1] Department of Integrative Systems Biology, George Washington University, Washington, DC, USA [2] Center for Genetic Medicine Research and Department of Pathology, Children's National Medical Center, Washington, DC, USA.
Oncogene. 2014 Nov 6;33(45):5295-302. doi: 10.1038/onc.2014.150. Epub 2014 Jun 9.
Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.
胸膜肺母细胞瘤是一种罕见的儿童期肺间充质细胞恶性肿瘤，可作为上皮囊肿保持休眠状态，或进展为高级别肉瘤。已描述了易患的种系功能丧失型DICER1变异。我们试图通过对15对肿瘤/正常样本进行全外显子组测序，随后进行靶向重测序、miRNA分析以及对其他肿瘤进行免疫组化分析，来发现其他相关因素。除了TP53频繁双等位基因缺失以及某些病例中的NRAS或BRAF突变外，每个病例都存在DICER1的复合破坏：一个种系（12例）或体细胞（3例）功能丧失变异加上RNase IIIb结构域中的一个体细胞错义突变。源自5p的微小RNA（miRNA）转录本保留了通常由DICER1去除的异常前体miRNA环序列。这项工作既定义了与DICER1突变相关联的遗传相互作用图谱，也为癌症中DICER1破坏导致的miRNA转录本改变提供了证据。
