Characteristics and Clinical Significance of TP53 Aberrations in Chronic Lymphocytic Leukemia

CARMEN STANGANELLI; IRMA SLAVUTSKY

Advances in Medicine and Biology

Nova Science Publishers Inc

Lugar: New York; Año: 2021; p. 177 - 206

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world, accounting for about 30% of all leukemias. It is a heterogeneous disease characterized by a highly variable clinical course and associated to several genetic markers that allow its subdivision into clinical relevant subgroups. TP53 (Tumor protein P53) deletions and mutations constitute important prognostic and predictive factors associated to adverse clinical outcome in CLL. The TP53 gene, located at 17p13, plays a central role in maintaining the genome integrity. It encodes a tumor suppressor protein that response to cellular stress, regulating the expression of target genes that participate in the control of the cell cycle, apoptosis, senescence, DNA repair and changes in metabolism. In this study, we have evaluated the presence of TP53 alterations in our cohort of 218 CLL patients, in order to analyze their frequency and distribution as well as their association with prognostic factors of the disease. Cytogenetic and FISH (Fluorescence in situ hybridization) analysis were performed. PCR and bidirectional Sanger sequencing were used to evaluate IGHV (immunoglobulin heavy variable region) and TP53 mutational status. Twenty-nine patients (12%) had TP53 aberrations. By FISH, del(17)(p13) was observed in 26 cases; 3 patients showed only TP53 mutations (TP53-M) and 10 cases TP53 deletion and mutation. Two deletions and two insertions (three frameshifts) (26.7%), and 11 point mutations (73.4%) (1 at the splicing site and 10 missense mutations), were found. As a whole, 13/15 (86.6%) variants were located in the DNA-binding domain (exons 4-8). The analysis of TP53-M patients showed association with unmutated IGHV (87.5% cases) and chromosome alterations (88.9%), including complex karyotypes, supporting the important genomic instability and poor outcome present in this group. It is important to point out the relevance to evaluate TP53 aberrations before starting each line of treatment, allowing for appropriate clinical decisions in order to optimize patient stratification and outcome. The deepening of these studies will allow a better understanding of the causes of the clinical variability present in CLL patients, making possible to improve the prediction of the disease outcome within the framework of a personalized medicine.