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Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma
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  • Julia Salmeron-Villalobos,
  • Juan Enric Ramis-Zaldivar,
  • Olga Balagué,
  • Jaime Verdú-Amorós,
  • Veronica Celis,
  • Constantino Sábado,
  • Marta Garrido,
  • Sara Mato,
  • Javier Uriz,
  • M. José Ortega,
  • Angela Gutierrez-Camino,
  • Daniel Sinnett,
  • Unai Illarregi,
  • Máxime Carron,
  • Alexandra Regueiro,
  • Ana María Galera Miñarro,
  • Blanca Gonzalez-Farré,
  • Elias Campo,
  • Noelia Garcia,
  • Dolors Colomer,
  • Itziar Astigarraga-Aguirre,
  • Mara Andrés,
  • Margarita Llavador,
  • Idoia Martin-Guerrero,
  • Itziar Salaverria
Julia Salmeron-Villalobos
Institut d'Investigacions Biomèdiques August Pi i Sunyer

Corresponding Author:jsalmeron@clinic.cat

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Juan Enric Ramis-Zaldivar
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Olga Balagué
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Jaime Verdú-Amorós
Hospital Clinico Universitario
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Veronica Celis
Hospital Sant Joan de Deu
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Constantino Sábado
Hospital Vall d'Hebron
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Marta Garrido
Hospital Vall d'Hebron
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Sara Mato
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Javier Uriz
Hospital Universitario de Donostia
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M. José Ortega
Hospital Universitario Virgen de las Nieves
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Angela Gutierrez-Camino
Centre Hospitalier Universitaire Sainte-Justine
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Daniel Sinnett
Centre Hospitalier Universitaire Sainte-Justine
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Unai Illarregi
UPV/EHU
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Máxime Carron
Centre Hospitalier Universitaire Sainte-Justine
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Alexandra Regueiro
Hospital Clinico Universitario de Santiago de Compostela
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Ana María Galera Miñarro
Hospital Clinico Universitario Virgen de la Arrixaca
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Blanca Gonzalez-Farré
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Elias Campo
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Noelia Garcia
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Dolors Colomer
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Itziar Astigarraga-Aguirre
Biocruces Bizkaia Health Research Institute
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Mara Andrés
Hospital La Fe
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Margarita Llavador
Hospital La Fe
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Idoia Martin-Guerrero
Biocruces Bizkaia Health Research Institute
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Itziar Salaverria
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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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 pediatric T-LBL are scarce and, therefore, its molecular landscape has not been fully elucidated yet. Procedure To characterize the genetic and molecular heterogeneity of paediatric T-LBL, 33 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 BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ to 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 latter being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favorable 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.
Nov 2022Published in Pediatric Blood & Cancer volume 69 issue 11. 10.1002/pbc.29926