Radovich Milan, Solzak Jeffrey P, Hancock Bradley A, Conces Madison L, Atale Rutuja, Porter Ryan F, Zhu Jin, Glasscock Jarret, Kesler Kenneth A, Badve Sunil S, Schneider Bryan P, Loehrer Patrick J
Department of Surgery, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 W Walnut Street, Room C312, Indianapolis, IN 46202, USA.
Br J Cancer. 2016 Feb 16;114(4):477-84. doi: 10.1038/bjc.2015.425. Epub 2016 Jan 14.
Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing.
The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used.
Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability.
A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855).
胸腺瘤是最罕见的诊断恶性肿瘤之一。为了更好地了解其生物学特性并确定治疗靶点，我们进行了下一代RNA测序。
对13例胸腺恶性肿瘤和3例正常胸腺进行RNA测序。在另一组35例胸腺恶性肿瘤中对微小RNA表达进行验证。对于基于细胞的研究，使用了胸腺瘤细胞系。
层次聚类显示基因表达簇与世界卫生组织（WHO）亚型之间100%一致。一个重要的区分因素是位于19号染色体长臂13.42区域的一个大型微小RNA簇，该簇在所有A型和AB型肿瘤中显著过表达，而在其他胸腺瘤和正常组织中几乎不表达。该微小RNA簇的过表达激活了PI3K/AKT/mTOR通路。用一组PI3K/AKT/mTOR抑制剂处理胸腺瘤AB细胞系导致细胞活力显著降低。
19号染色体长臂13.42区域的一个大型微小RNA簇是A型和AB型胸腺瘤的转录标志。此外，该簇激活PI3K通路，提示可能对这些肿瘤亚型患者探索PI3K抑制剂。这项工作已促成了一项针对复发或难治性胸腺瘤的PI3K抑制II期临床试验的启动（http://clinicaltrials.gov/ct2/show/NCT02220855）。
