Complex genetic landscape in CLL: Clinical impact on patients’ survival and insights into the altered molecular pathways

Chronic lymphocytic leukemia (CLL) is characterized by a remarkably complex landscape. We performed a molecular characterization of liquid biopsies from 137 leukemia samples and 10 healthy subjects. Almost all patients express single-nucleotide polymorphism (SNP) mutations of the <i>TP53</i> gene and the most common (<i>n</i> = 132 patients) was the Pro72Arg missense mutation. It was associated with significantly higher overall survival (<i>p</i> < 0.001) in untreated patients (<i>n</i> = 73) compared to treated patients (<i>n</i> = 58). However, this TP53 mutation is identified in both patients and healthy volunteers being likely a germinal mutation classified as SNP. In addition, a rare missense SNP mutation (Arg337Cys) of <i>TP53</i> gene, correlated positively with clinical outcome (204 months; <i>p</i> = 0.00001) was also found. Its effects on p53 stability and function were subsequently evaluated. A missense mutation (Met541Leu) in the <i>KIT</i> gene was found in 18 patients and it was also significantly associated (<i>p</i> < 0.05) with a favorable outcome in untreated patients (<i>n</i> = 10) compared to treated ones (<i>n</i> = 8). We performed a comparative analysis among CLL patients classified into three prognostic groups (Binet A, B, and C). Survival analysis confirmed that Binet C patients had a significantly reduced survival compared to Binet A patients (<i>p</i> < 0.05).