Clinical Significance of Genomic Landscape in Pediatric Advanced MDS

Pediatric advanced myelodysplastic syndrome (MDS) is characterized by a dismal prognosis and a high frequency of mutations. In this study we aimed to assess the clinical significance of genomic landscape in pediatric advanced MDS. We performed next generation sequencing on the bone marrow sample of 72 children with diagnoses of advanced MDS, including RAEB(n=54) and RAEB-T(n=18), targeting genes closely associated with MDS or other hotspots from adult and pediatric myeloid neoplasms.

With only mutations with presumed functional consequences being considered, 83.3% of patients carried gene mutation. We found frequent mutations in PTPN11 (16 cases, 22.2%), SETBP1(14 cases, 19.4%), NRAS (12 cases, 16.7%), RUNX1(10 cases, 13.9%), NF1(9 cases, 12.5%), FLT3(8 cases, 11.1%), GATA2(8 cases, 11.1%), WT1(8 cases, 11.1%). PTPN11 was the most commonly mutated gene. In total, genes involved in the RAS/MAPK pathway, were the most common gene mutations（32 cases,44.4%). We found significant co-occurrence between PTPN11 and NF1 mutations (P=0.003), SETBP1 and EZH2 mutations (P=0.021), SETBP1 and GATA2 mutations (P=0.041), FLT3 and WT1 mutations (P=0.026). SETBP1 and GATA2 alterations were frequently detected in patients with monosomy 7(P<0.001). Children with mutations involved in the RAS-MAPK pathway displayed elevated blast percentages in both BM (14.25% VS 8%, P=0.018) and PB (4% VS 1%, P=0.024), and they also demonstrated a significantly higher likelihood of detecting splenomegaly (P = 0.007). A total of 63 children were available for follow-up. The median follow-up of the entire cohort of children was 27 months (range, 1-116 months). Although not statistically significant, alterations in PTPN11 appeared to be linked with an unstable disease progression. Children with PTPN11 mutations who did not undergo HSCT died within 3 to 18 months after diagnosis, except for one who was lost to follow-up three months post-diagnosis. In contrast, those who underwent HSCT achieved complete remission and remained alive at the last follow-up. Mutations in PTPN11 were significantly correlated with unfavorable EFS (HR:2.909, 95%CI: 1.303-6.495, P=0.009). Patients with mutated genes involved in the RAS/MAPK pathway exhibited similar event-free survival (EFS) and overall survival (OS) compared to those without such mutations. Overall, mutations in RAS/MAPK pathway are the most common genetic alterations in advanced pediatric MDS. PTPN11 alterations were associated with unfavorable EFS.

No relevant conflicts of interest to declare.