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14-05-2024 | Chronic Lymphocytic Leukemia | Research

Genetic variability profiling of the p53 signaling pathway in chronic lymphocytic leukemia. Individual and combined analysis of TP53, MDM2 and NQO1 gene variants

Authors: María Belén Fontecha, María Del Rosario Anadón, Verónica Mercado Guzmán, Carmen Stanganelli, Camila Galvano, Fernanda Tosin, Javier Bordone, Raimundo Bezares, Cecilia Rodríguez, Viviana Heller, Irma Slavutsky, Ariela Freya Fundia

Published in: Annals of Hematology

Abstract

TP53 gene disruption, including 17p13 deletion [del(17p)] and/or TP53 mutations, is a negative prognostic biomarker in chronic lymphocytic leukemia (CLL) associated with disease progression, treatment failure and shorter survival. Germline variants in p53 signaling pathway genes could also lead to p53 dysfunction, but their involvement in CLL has not been thoroughly evaluated. The aim of this study was to determine the association of TP53, MDM2 and NQO1 gene variability with clinical and genetic data of CLL patients. Individual genotype and haplotype data of CLL patients were compared with clinical prognostic factors, cytogenetic and molecular cytogenetic findings as well as IGHV and TP53 mutational status. The study included 116 CLL patients and 161 healthy blood donors. TP53 (rs1042522, rs59758982, rs1625895), NQO1 (rs1800566) and MDM2 (rs2279744, rs150550023) variants were genotyped using different PCR approaches. Analysis of genotype frequencies revealed no association with the risk of CLL. TP53 rs1042522, rs1625895 and MDM2 rs2279744 variants were significantly associated with abnormal karyotype and the presence of del(17p). Similarly, these two TP53 variants were associated with TP53 disruption. Moreover, TP53 C-A-nondel and G-A-del haplotypes (rs1042522-rs1625895-rs59758982) were associated with an increased likelihood of carrying del(17p) and TP53 disruptions. MDM2 T-nondel haplotype (rs2279744-rs150550023) was found to be a low risk factor for del(17p) (OR = 0.32; CI: 0.12–0.82; p = 0.02) and TP53 disruptions (OR = 0.41; CI: 0.18–0.95; p = 0.04). Our findings suggest that TP53 and MDM2 variants may modulate the risk to have chromosome alterations and TP53 disruptions, particularly del(17p). To our knowledge this is the first study of several germline variants in p53 pathway genes in Argentine patients with CLL.

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Title: Genetic variability profiling of the p53 signaling pathway in chronic lymphocytic leukemia. Individual and combined analysis of TP53, MDM2 and NQO1 gene variants
Authors: María Belén Fontecha
María Del Rosario Anadón
Verónica Mercado Guzmán
Carmen Stanganelli
Camila Galvano
Fernanda Tosin
Javier Bordone
Raimundo Bezares
Cecilia Rodríguez
Viviana Heller
Irma Slavutsky
Ariela Freya Fundia
Publication date: 14-05-2024
Publisher: Springer Berlin Heidelberg
Keyword: Chronic Lymphocytic Leukemia
Published in: Annals of Hematology
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-024-05794-w

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