背景:T细胞淋巴母细胞淋巴瘤(T-LBL)是一种与T细胞急性淋巴细胞白血病(T-ALL)密切相关的侵袭性肿瘤。尽管他们有相似之处,与T-ALL相反,关于儿科T-LBL的研究很少,因此,其分子景观尚未完全阐明。因此,这项研究的目的是表征儿科T-LBL的遗传和分子异质性,并评估区分该实体和T-ALL的新型分子标记.
方法:使用综合方法分析了33例儿科T-LBL患者,包括靶向的下一代测序,RNA测序转录组分析和拷贝数阵列。
结果:拷贝数和突变分析允许检测9p/CDKN2A的复发性纯合缺失(78%),三体20(19%)和17q24-q25(16%)的收益,以及NOTCH1的频繁突变(62%),其次是BCL11B(23%),WT1(19%)和FBXW7,PHF6和RPL10基因(15%,分别)。在突变发生率和全球基因组复杂性水平方面,这种遗传特征与T-ALL中描述的没有区别。但在T-LBL中公布了几乎独家的17q25收益和Trisomy20。此外,我们在儿科T-LBL中发现了新的基因融合,包括NOTCH1-IKZF2,RNGTT-SNAP91和DDX3X-MLLT10,最后一个是T-ALL中先前描述的唯一一个。此外,临床相关性强调了Notch通路改变的存在是与有利结局相关的一个因素.
结论:总之,儿科T-LBL的基因组景观与T-ALL中观察到的相似,Notch信号通路失调仍是其发病机制的基石,不仅包括突变,还包括靶向NOTCH1的融合基因。
BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL.
METHODS: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays.
RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome.
CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.