Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T‐cell lymphoblastic lymphoma

Abstract 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. Procedure 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 .