NOTCH1 and TP53 mutations in chronic lymphocytic Leukemia. Their relationship with cytogenetics, FISH and IGHV status

PATRICIA DOS SANTOS; CAMILA GALVANO; IRMA SLAVUTSKY; CARMEN STANGANELLI; ANDREA KRZYWINSKI

Mar del Plata

Congreso; LVIII Reunión Annual de la Sociedad Argentina de Investigación Clínica; 2018

Sociedad Argentina de Investigación Clínica

Molecular studies have revealed a number of recurrently mutated genes in chronic lymphocytic leukemia (CLL). Among them, the study of NOTCH1 and TP53 gene mutations showed significant importance in CLL prognosis. The aim of this study was to evaluate NOTCH1 and TP53 mutations in our CLL patients, in order to analyze the type and frequency of these alterations. Results were correlated with cytogenetics, FISH and IGHV mutational status studies. A total of 60 patients were evaluated. Mutational status was analyzed by PCR followed by bidirectional sequencing, and compared with public databases. The study was approved by the Institutional Ethics Committee. All individuals provided their informed consent. Three (5%) cases showed the NOTCH1 c.7541_7542delCT mutation. These patients had unmutated (UM) IGHV (100% germinal identity) and two of them showed very complex karyotypes. For TP53 mutation analysis, a selected group of 24 patients with TP53 deletion by FISH analysis was evaluated. Nine (37.5%) cases showed mutated TP53 (TP53-M), all of them with more than 20% of cells with TP53 deletion; exons 4-8 were involved. Two insertions and 2 deletion with change of reading frame, and 5 replacement point mutations (4 transitions and 1 transversion), were observed. The polymorphism analysis of codon 72 (rs1042522) that encodes arginine (Arg) or proline (Prol) showed association of the Pro/Pro genotype with TP53-M (p=0.047). The presence of TP53-M was not significantly related to IGVH mutational status. Cytogenetic analysis showed that total cases with TP53-M had abnormal karyotypes, compared to 25% patients with TP53-UM. One case had both NOTCH1 and TP53 mutations. Our data constitute the first evaluation of NOTCH1 and TP53 mutations in patients with CLL in our country and provide information about the molecular heterogeneity of this pathology.