Hamann Martin V, Godbole Shweta, Adiba Maisha, Leddy Sabrina M, Navolić Jelena, Tabatabai Ghazaleh, Merk Daniel J, Lange Ulrike C, Neumann Julia E
Leibniz Institute of Virology (LIV), Hamburg, Germany.
Department of Pathology, Research and Diagnostic Center (RDC), Amsterdam University Medical Center, Amsterdam, The Netherlands.
Acta Neuropathol Commun. 2025 Jul 22;13(1):159. doi: 10.1186/s40478-025-02078-w.
Atypical teratoid rhabdoid tumors (ATRTs) are aggressive central nervous system tumors mainly affecting young children. Extensive molecular characterization based on gene expression and DNA methylation patterns has solidly established three major ATRT subtypes (MYC, SHH and TYR), which show distinct clinical features, setting the basis for more effective, targeted treatment regimens. Transcriptional activity of transposable elements (TEs), like LINE1s and LTRs, is tightly linked with human cancers as a direct consequence of lifting epigenetic repression over TEs. The sole recurrent biallelic loss-of-function mutation in SMARCB1 in ATRTs, a core component of the SWI/SNF chromatin remodeling complex, raises the question of how TE transcription contributes to ATRT development. Here, we comprehensively investigate the transcriptional profiles of 1.9M LINE1 and LTR elements across ATRT subtypes in primary human samples. We find TE transcription profiles allow sample stratification into ATRT subtypes. The TE activity signature in the ATRT-MYC subtype is unique, setting these tumors apart from SHH and TYR ATRTs. More specifically, ATRT-MYC show broadly reduced transcript levels of LINE1 and ERVL-MaLR subfamilies. ATRT-MYC also displayed significantly less LTR and LINE1 loci with bidirectional promoter activity. Furthermore, we identify 849 differentially transcribed TEs in primary samples, which are predictive towards established ATRT-SHH and -MYC cell line models. In summary, including TE transcription profiles into the molecular characterization of ATRTs might reveal new tumor vulnerabilities leading to novel therapeutic interventions, such as immunotherapy.
非典型畸胎样横纹肌样瘤（ATRTs）是主要影响幼儿的侵袭性中枢神经系统肿瘤。基于基因表达和DNA甲基化模式的广泛分子特征分析已牢固确立了三种主要的ATRT亚型（MYC、SHH和TYR），它们具有不同的临床特征，为更有效、有针对性的治疗方案奠定了基础。转座元件（TEs），如长散在核元件1（LINE1s）和长末端重复序列（LTRs）的转录活性与人类癌症紧密相关，这是对TEs的表观遗传抑制解除的直接后果。ATRTs中SMARCB1的唯一复发性双等位基因功能丧失突变是SWI/SNF染色质重塑复合物的核心组成部分，这就提出了TE转录如何促进ATRT发生发展的问题。在此，我们全面研究了原发性人类样本中190万个LINE1和LTR元件在ATRT亚型中的转录谱。我们发现TE转录谱可将样本分层为不同的ATRT亚型。ATRT-MYC亚型中的TE活性特征是独特的，使这些肿瘤与SHH和TYR ATRTs区分开来。更具体地说，ATRT-MYC中LINE1和ERVL-MaLR亚家族的转录水平普遍降低。ATRT-MYC中具有双向启动子活性的LTR和LINE1位点也明显较少。此外，我们在原发性样本中鉴定出849个差异转录的TEs，它们对已建立的ATRT-SHH和-MYC细胞系模型具有预测性。总之，将TE转录谱纳入ATRTs的分子特征分析可能会揭示新的肿瘤脆弱性，从而带来新的治疗干预措施，如免疫疗法。
