%0 Journal Article
%T Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.
%A Salmerón-Villalobos J
%A Ramis-Zaldivar JE
%A Balagué O
%A Verdú-Amorós J
%A Celis V
%A Sábado C
%A Garrido M
%A Mato S
%A Uriz J
%A Ortega MJ
%A Gutierrez-Camino A
%A Sinnett D
%A Illarregi U
%A Carron M
%A Regueiro A
%A Galera A
%A Gonzalez-Farré B
%A Campo E
%A Garcia N
%A Colomer D
%A Astigarraga I
%A Andrés M
%A Llavador M
%A Martin-Guerrero I
%A Salaverria I
%J Pediatr Blood Cancer
%V 69
%N 11
%D Nov 2022
%M 36000950
%F 3.838
%R 10.1002/pbc.29926
%X 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.