CAT RS1001179 SINGLE NUCLEOTIDE POLYMORPHISM IDENTIFIES AN AGGRESSIVE CLINICAL BEHAVIOR IN CHRONIC LYMPHOCYTIC LEUKEMIA

Chronic lymphocytic leukemia (CLL) is an incurable disease char- acterized by a highly variable clinical course, with some patients hav- ing indolent disease and others experiencing a more accelerated course, treatment resistance and a dismal outcome. We have recently identified low catalase (CAT) expression as a major antioxidant ele- ment that identifies an indolent clinical behavior in CLL. In contrast, high CAT expression is associated with a more aggressive disease course. Moreover, we have shown that CLL cells harboring the rs1001179 single nucleotide polymorphism (SNP) T allele in the CAT promoter exhibit a significantly higher CAT expression com- pared with cells bearing the CC genotype. The objective of this study was to investigate the prognostic significance of the CAT rs1001179 SNP in CLL. We studied 235 patients with CLL and 123 healthy donors (HDs). Genotyping was assessed by restriction fragment length polymorphism (RFLP)-PCR. Time to first treatment (TTFT) curves were estimated using the Kaplan-Meier method and compared using the log-rank test. The distribution of genotypes was consistent with the Hardy–Weinberg equilibrium among CLL patients and HDs (χ2=0.156, P>0.05; χ2=0.099, P>0.05; respectively), and no signifi- cant differences in genotype frequencies was found. The mutant ho- mozygous TT genotype identified a subgroup of CLL patients with a more aggressive disease and a shorter TTFT whereas the CC and CT genotypes were associated with an indolent disease course (CC/CTvs TT: P=0.0096; Figure 1). Furthermore, TT genotype refines risk stratification in patients with indolent disease, defined by low ZAP70 expression (CC/CT vs TT: P<0.0001), favorable/neutral cytogenetics (CC/CTvs TT: P=0.0004) and Binet A stage (CC/CTvs TT: P=0.0383). Consis- tently, we have documented that patients bearing the TT genotype were characterized by a higher % of lymphocytes; a lower count of red blood cells, hemoglobin, and platelets at diagnosis compared with patients bearing the CC/CT genotype. Remarkably, the TT genotype identified a subgroup of CLL patients with a faster clinical progression within early-stage disease subgroups of patients char- acterized by lower CD38 expression and wild-type p53 (CC/CTvs TT: P=0.0514; CC/CTvs TT: P=0.0560; respectively). This study shows for the first time that the TT genotype of CAT rs1001179 SNP identifies CLL patients with a poor prognosis and provides prog- nostic information on disease progression in patients with early- stage disease.