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Molecular and clinicopathologic features of gliomas harboring NTRK fusions.
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2020-07-14 , DOI: 10.1186/s40478-020-00980-z
Matthew Torre 1, 2 , Varshini Vasudevaraja 3 , Jonathan Serrano 3 , Michael DeLorenzo 3 , Seth Malinowski 4 , Anne-Florence Blandin 4 , Melanie Pages 5 , Azra H Ligon 1, 6 , Fei Dong 1 , David M Meredith 1 , MacLean P Nasrallah 7 , Craig Horbinski 8, 9 , Sonika Dahiya 10 , Keith L Ligon 1, 2, 4 , Mariarita Santi 7, 11 , Shakti H Ramkissoon 12, 13 , Mariella G Filbin 14 , Matija Snuderl 3 , Sanda Alexandrescu 1, 2
Affiliation  

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

中文翻译:

具有 NTRK 融合的神经胶质瘤的分子和临床病理学特征。

在≤2% 的神经胶质瘤中检测到涉及神经营养性酪氨酸受体激酶 (NTRK) 基因的融合,并且可以促进神经胶质瘤形成。TRK 抑制剂是食品和药物管理局批准的首批针对 NTRK 融合神经胶质瘤的靶向疗法之一,其显着的治疗效果已引起临床对表征这些肿瘤的兴趣。在这项对 42 个神经胶质瘤进行 NTRK 融合的多机构回顾性研究中,下一代 DNA 测序 (n = 41)、下一代 RNA 测序 (n = 1)、RNA 测序融合 panel (n = 16)、甲基化谱分析 (n = 18),并进行了组织学评估 (n = 42)。所有婴儿 NTRK 融合神经胶质瘤 (n = 7) 都具有高级组织学,除一个例外,没有其他显着的遗传改变。儿科 NTRK 融合神经胶质瘤 (n = 13) 通常涉及 NTRK2,组织学分级从低到高不等,并证明与促纤维增生性婴儿神经节胶质瘤、毛细胞星形细胞瘤、神经节胶质瘤和胶质母细胞瘤等实体有组织学重叠,但它们很少与已知的甲基化类别家族或相互之间高度匹配;涉及 ATRX、PTEN 和 CDKN2A/2B 的改变存在于一部分病例中。成人 NTRK 融合神经胶质瘤 (n = 22) 通常涉及 NTRK1 并且主要具有高级组织学;涉及 IDH1、ATRX、TP53、PTEN、TERT 启动子、RB1、CDKN2A/2B、NF1 和多体 7 的遗传改变很常见。甲基化图谱的无监督主成分分析表明,组织学分级、涉及的 NTRK 基因或年龄组没有明显的分组。KEGG 通路分析检测到 PI3K/AKT、MAPK、和其他途径。总之,该研究强调了 NTRK 融合神经胶质瘤的临床、组织学和分子异质性,尤其是按年龄组分层时。
更新日期:2020-07-14
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