Genetic Variants in p53 Signaling Pathway Influence Treatment Outcome in Chronic Myeloid Leukemia

MARIA DEL ROSARIO ANADON; MARIA BELEN FONTECHA; NATALIA WEICH; BEATRIZ MOIRAGHI; RAQUEL BENGIÓ; IRENE LARRIPA; ARIELA FUNDIA

Montpellier

Congreso; 23rd Annual John Goldman E-Conference on Chronic Myeloid Leukemia: Biology and Therapy,; 2021

The p53 protein, a key tumor suppressor and transcription factor, coordinates cellular responses to stress by regulating cell cycle arrest, apoptosis and DNA damage response. p53 activity is negatively regulated mainly by MDM2 gene and also by NQO1, among other genes. Inactivation of the p53 pathway due to somatic and/or germline variants was associated with genomic instability, cancer risk, disease progression and chemotherapy resistance. In chronic myeloid leukemia (CML), driven by the BCR-ABL1 oncogene, p53 mutations were seldom observed in chronic phase, but were detected in ~30% of patients with myeloid blast crisis. CML progression and treatment failure with tyrosine kinase inhibitors (TKIs), as well as resistance onset are mainly driven by ABL1 kinase domain point mutations. Additionally, clonal chromosomal evolution, BCR-ABL1 amplification, pharmacogenomic variations or activation of specific signaling pathways, have also been described. We and others have shown that TP53 rs1042522 influences TKIs treatment. However, variants in p53 non-coding regions that can modify p53 activity and p53 regulators have not been well-studied in CML.AimsTo evaluate the contribution of genetic variants in p53 signaling pathway in the response to TKIs in CML patients from Argentina by evaluating MDM2 and NQO1 p53 regulators and two intronic TP53 variants.MethodsA total of 144 CML treated patients were evaluated. Treatment response was defined considering the European LeukemiaNet. The study was approved by the Institutional Ethics Committee and conducted in accordance with the Declaration of Helsinki. Nine variants were genotyped by different PCR methods and direct sequencing. TP53 rs17878362 and rs1625895; NQO1 rs1800566 and 5 in MDM2 gene: rs2279744, rs117039649, rs7484572, rs150550023 and rs1196333 were evaluated. Statistical analysis was performed with χ2 test, Fisher´s test and survival curves were estimated by Kaplan-Meier method and the Log Rank test, with a significance of p0.05). As no minor alleles were detected for MDM2 rs117039649 and rs7484572, they were excluded from further analyses. TKIs failure was detected in 66 patients, 28 of them exhibited ABL1 mutations. No significant associations were found between genotype and allelic distributions with clinical-pathological data such as age, gender, disease phase, Sokal, cytogenetic response (MR2), treatment failure with the first line TKI or ABL1 mutations.Individual analysis of each variant showed that patients with NQO1 rs1800566 TT genotype exhibited an increased risk of treatment failure (OR: 3.39; 95% CI: 1.2- 9.9; p = 0.032). Non-responder cases carrying MDM2 rs150550023 nondel/nondel genotype were associated with an inferior rate of Overall Survival (OS) (p=0.017). Furthermore, patients carrying two genotypes with MDM2 rs150550023-del and rs2279744-G alleles were associated with a higher rate of OS (p=0.014).ConclusionsThese preliminary data suggest that MDM2 and NOQ1 variants, individually or in combination, could modulate TKIs response and, thereby, could probably facilitate disease progression. In case of validating these findings in a larger cohort, these markers could allow the identification of patients more likely to have worse outcome, enabling treatment switching.