Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype

Autor: Julie Bruneau, Véronique Avettand-Fenoel, Ludovic Lhermitte, Morgane Cheminant, Felipe Suarez, Keith Durkin, Maria Artesi, Ambroise Marçais, Olivier Hermine, David Sibon, Vahid Asnafi, Cécile Laurent, Michel Georges, Nicolas Rosewick, Anne Van den Broeke, Claudine Pique, Vincent Hahaut
Přispěvatelé: Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Inserm U1016, Institut Cochin, Paris, France, 22 Rue Méchain, 75014 Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Sorbonne-Paris-Cité, Paris, France, Laboratoire de Recherche d'Hémobiologie Cochin, Hôpital Cochin, Paris, France.
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Leukemia
Leukemia, Nature Publishing Group: Open Access Hybrid Model Option B, 2020, ⟨10.1038/s41375-020-0900-3⟩
ISSN: 0887-6924
1476-5551
Popis: International audience; Adult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation.
Databáze: OpenAIRE
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