Impact of mutations inFLT3, PTPN11andRASgenes on the overall survival of pediatric B cell precursor acute lymphoblastic leukemia in Brazil

Abstract

We analyzed mutations in four genes (FLT3, KRAS/NRAS and PTPN11) that might disrupt the RAS/mitogen activated protein kinase (MAPKinase) signaling pathway, to evaluate their prognostic value in children younger than 16 years old with B-cell precursor acute lymphoblastic leukemia (Bcp-ALL). The overall survival (OS) was determined with the Kaplan-Meier method. MAPKinase genes were mutated in 25.4% and 20.1% of childhood and infant Bcp-ALL, respectively. Children with hyperdiploidy were more prone to harboring a MAPKinase gene mutation (odds ratio [OR] 3.18; 95% confidence interval [CI] 1.07-9.49). The mean OS of all cases was 54.0 months. FLT3 and PTPN11 mutations had no impact on OS. K/NRAS mutations were strongly associated with MLL-AFF1 (OR 5.78; 95% CI 1.00-33.24), and conferred poorer OS (p = 0.034) in univariate analysis.

Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B‐precursor acute lymphoblastic leukemia

“…Barbosa et al. reported that 15.8% (3/19) of hyperdiploid (defined by DNA index of ≥1.16) ALL displayed PTPN11 mutations, whereas the frequency was 3.4% (two of 59) in patients with nonhyperdiploid ALL . In our study, PTPN11 mutations occurred in 3.0% (16/526) of all pediatric B‐precursor ALL and 3.4% (2/59) of hyperdiploid ALL.…”

“…In our study, PTPN11 mutations occurred in 3.0% (16/526) of all pediatric B‐precursor ALL and 3.4% (2/59) of hyperdiploid ALL. The frequency of PTPN11 mutations was much lower than that reported from the small Brazilian series and a large cohort from Italy . The definition of hyperdiploidy was different among these studies; we used karyotyping to identify hyperdiploid ALL with a chromosomal number of 51–68, whereas the previous studies used DNA index by flow cytometry.…”

“…Recently, Barbosa et al. examined 134 children with B‐precursor ALL and found that none of the 31 patients carrying ETV6‐RUNX1 , TCF3‐PBX1 , or BCR‐ABL1 had K/NRAS mutations . Our study enrolled 535 pediatric B‐precursor ALL patients, with recurrent molecular genetic data available for almost all patients, which allowed us to make a more relevant correlation analysis.…”

“…PTPN11 mutations were present in 35% of juvenile myelomonocytic leukemia and less frequent in other leukemias . The frequency of PTPN11 mutations in B‐precursor ALL was reported to be around 6.0–9.5% . Tartaglia et al.…”

Proteomics‐based discovery of biomarkers for paediatric acute lymphoblastic leukaemia: challenges and opportunities

“…Risk‐based therapy is emphasized in therapeutic protocols for paediatric ALL to reduce the toxicity in patients with low risk and provide aggressive therapies for those with high risk. Age, initial white blood cells, ALL subtype, chromosomal aberrations, or MRD have been considered in the risk stratification, although the exact disease‐specific and sensitive biomarkers remain unknown . Proteomics is an opening and new window to make the discovery and identification of protein‐based biomarkers possible in paediatric ALL‐relapses, and a useful tool to develop individual and personalized therapies .…”