The spectrum of subclonal TP53 mutations in chronic lymphocytic leukemia: A next generation sequencing retrospective study.
Next Generation Sequencing
TP53
chronic lymphocytic leukemia
heterogeneity
subclonal mutations
Journal
Hematological oncology
ISSN: 1099-1069
Titre abrégé: Hematol Oncol
Pays: England
ID NLM: 8307268
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
revised:
30
07
2022
received:
05
04
2022
accepted:
01
08
2022
pubmed:
13
8
2022
medline:
15
12
2022
entrez:
12
8
2022
Statut:
ppublish
Résumé
Chronic lymphocytic leukemia (CLL) is a hematological disorder with complex clinical and biological behavior. TP53 mutational status and cytogenetic assessment of the deletion of the corresponding locus (17p13.1) are considered the most relevant biomarkers associated with pharmaco-predictive response, chemo-refractoriness, and worse prognosis in CLL patients. The implementation of Next Generation Sequencing (NGS) methodologies in the clinical laboratory allows for comprehensively analyzing the TP53 gene and detecting mutations with allele frequencies ≤10%, that is, "subclonal mutations". We retrospectively studied TP53 gene mutational status by NGS in 220 samples from 171 CLL patients. TP53 mutations were found in 60/220 (27.3%) samples and 47/171 (27.5%) patients. Interestingly, subclonal mutations could be detected in 31/60 samples (51.7%) corresponding to 25 patients (25/47, 53.2%). We identified 44 distinct subclonal TP53 mutations clustered in the central DNA-binding domain of p53 protein (exons 5-8, codons 133-286). Missense mutations were predominant (>80%), whereas indels, nonsense, and splice site variants were less represented. All subclonal TP53 variants but one [p.(Pro191fs)] were already described in NCI and/or Seshat databases as "damaging" and/or "probably damaging" mutations (38/44, 86% and 6/44, 14%, respectively). Longitudinal samples were available for 37 patients. Almost half of them displayed at least one TP53 mutant subclone, which could be alone (4/16, 25%) or concomitant with other TP53 mutant clonal ones (12/16, 75%); different patterns of mutational dynamics overtimes were documented. In conclusion, utilization of NGS in our "real-life" cohort of CLL patients demonstrated an elevated frequency of subclonal TP53 mutations. This finding indicates the need for precisely identifying these mutations during disease since the clones carrying them may become predominant and be responsible for therapy failures.
Identifiants
pubmed: 35961859
doi: 10.1002/hon.3063
pmc: PMC10086786
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
TP53 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
962-975Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
Organisme : Compagnia di San Paolo
Organisme : Gilead Sciences
Organisme : Associazione Italiana Contro le Leucemie-Linfomi e Mieloma
Organisme : Ministero della Salute
Informations de copyright
© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
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