1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA. [2].
Nat Genet. 2013 Oct;45(10):1141-9. doi: 10.1038/ng.2734. Epub 2013 Aug 5.
Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
胶质母细胞瘤是最难治疗的癌症之一。在这里，我们描述了一个计算平台，该平台整合了拷贝数变异和体细胞突变的分析，并揭示了胶质母细胞瘤中框内基因融合的全景。我们发现 LZTR1 中存在杂合性缺失的突变，该基因编码 CUL3 包含的 E3 连接酶复合物的衔接子。突变和缺失破坏了 LZTR1 的功能，从而抑制了保留干细胞特征的神经胶质瘤球体的自我更新和生长。CTNND2 的功能丧失突变靶向神经特异性基因，并与沿非常侵袭性间充质表型的神经胶质瘤细胞的转化相关。我们还报告了经常发生的易位，将 EGFR 的编码序列与几个伙伴融合，其中 EGFR-SEPT14 是人类胶质母细胞瘤中最常见的功能性基因融合。EGFR-SEPT14 融合激活 STAT3 信号通路，并赋予有丝分裂原独立性和对 EGFR 抑制的敏感性。这些结果提供了对胶质母细胞瘤发病机制的深入了解，并突出了治疗干预的新靶点。
