二代测序技术检测儿童急性淋巴细胞白血病的基因突变谱及其预后意义

OBJECTIVE: This study analyzed the correlation between genetic mutation and prognostic significance in childhood acute lymphoblastic leukemia (ALL). METHODS: Targeted exome by next-generation sequencing (NGS) technology was used to carry out molecular profiling of untreated 141 children with ALL in Fujian Medical University Union Hospital from November 2016 to December 2019. Correlation of genetic features and clinical features and outcomes was analyzed. RESULTS: Among the 141 pediatric patients with ALL, 160 somatic mutations were detected in 83 patients (58.9％), including 37 grade Ⅰ mutations and 123 grade Ⅱ mutations. Single nucleotide variation was the most common type of mutation. KRAS was the most common mutant gene (12.5％), followed by NOTCH1 (11.9％), and NRAS (10.6％). RAS pathway (KRAS, FLT3, PTPN11), PAX5 and TP53 mutations were only detected, and NRAS mutations was mainly found in B-ALL while FBXW7 and PTEN mutations were only found, and NOTCH1 mutation was mainly detected in T-ALL. The average number of mutations detected in each child with T-ALL was significantly higher than in children with B-ALL (4.16±1.33 vs 2.04±0.92, P＝0.004). The children were divided into mutation and non-mutation groups according to the presence or absence of genetic variation. There were no statistically significant differences in sex, age, newly diagnosed white blood cell count, minimal or measurable residual disease monitoring results, expected 3-year event-free survival (EFS) and overall survival (OS) between the two groups (P>0.05). On the other hand, the proportion of T-ALL and fusion gene negative children in the mutant group was significantly higher than the non-mutation group (P＝0.021 and 0.000, respectively). Among the patients without fusion gene, the EFS of children with grade I mutation was significantly lower than children without grade I mutation (85.5％ vs 100.0％, P＝0.039). Among children with B-ALL, the EFS of those with TP53 mutation was significantly lower than those without TP53 mutation (37.5％ vs 91.2％, P<0.001). CONCLUSION: Genetic variation is more common in childhood ALL and has a certain correlation with clinical phenotype and prognosis. Therefore, targeted exome by NGS can be used as an important supplement to the traditional morphology, immunology, cytogenetics, and molecular biology classification．