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

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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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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors wish to thank the patients and controls for their participation in this study.

Funding

The present work was partly funded by the CONICET (National Scientific and Technical Research Council) grant numbers: PUE 2018-0042 (IS) and PIP 2021 − 1779 (AFF, IS). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Laboratorio de Farmacogenómica, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina

    María Belén Fontecha, María Del Rosario Anadón, Verónica Mercado Guzmán & Ariela Freya Fundia

  2. Laboratorio de Biología Molecular, Hospital Alemán, Buenos Aires, Argentina

    Verónica Mercado Guzmán

  3. División Patología Molecular, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina

    Carmen Stanganelli

  4. Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina

    Camila Galvano & Irma Slavutsky

  5. Servicio de Hematología, Hospital El Cruce, Buenos Aires, Argentina

    Fernanda Tosin & Javier Bordone

  6. Servicio de Hematología, Hospital Álvarez, Buenos Aires, Argentina

    Raimundo Bezares

  7. Facultad de Ciencias Médicas, Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    Cecilia Rodríguez & Viviana Heller

  8. Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain

    Ariela Freya Fundia

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  1. María Belén Fontecha
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Contributions

MBF, MRA, VMG, CS, CG and CR participate in the acquisition, analysis, and interpretation of data; FT, JB, RB, and VH were responsible for clinical data collection and follow up of patients; MBF, AF and IS were responsible for the study conceptualization, writing the first draft of the manuscript, review and editing the final version. All authors read and approved the final version of the manuscript.

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Correspondence to María Belén Fontecha or Ariela Freya Fundia.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the National Academy of Medicine from Buenos Aires, Argentina (Nº 32/23/CEIANM). Informed consent was obtained from all individual participants included in the study.

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Fontecha, M.B., Anadón, M.D.R., Mercado Guzmán, V. et al. Genetic variability profiling of the p53 signaling pathway in chronic lymphocytic leukemia. Individual and combined analysis of TP53, MDM2 and NQO1 gene variants. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05794-w

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