Abstract
BackgroundAcute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give rise to ALL remain poorly understood.MethodsUsing next-generation sequencing (NGS) in matched germline and tumor samples from 140 pediatric Chinese patients with ALL, we landscaped the gene mutations and estimated the mutation frequencies in this disease.ResultsOur results showed that the top driver oncogenes having a mutation prevalence over 5% in childhood ALL included KRAS (8.76%), NRAS (6.4%), FLT3 (5.7%) and KMT2D (5.0%). While the most frequently mutated genes were KRAS, NRAS and FLT3 in B cell ALL (B-ALL), the most common mutations were enriched in NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) in T cell ALL (T-ALL). These mutant genes are involved in key molecular processes, including the Ras pathway, the Notch pathway, epigenetic modification, and cell-cycle regulation. Strikingly, more than 50% of mutations occurred in the high-hyperdiploid (HeH) ALL existed in Ras pathway, especially FLT3 (20%). We also found that the epigenetic regulator gene KMT2D, which is frequently mutated in ALL, may be involved in driving leukemia transformation, as evidenced by an in vitro functional assay.ConclusionOverall, this study provides further insights into the genetic basis of ALL and shows that Ras mutations are predominant in childhood ALL, especially in the high-hyperdiploid subtype in our research.
Highlights
Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication
Somatic mutations in newly diagnosed ALL patients To better understand the landscape of somatic mutations in Chinese children with ALL, we performed targeted sequencing of 140 pediatric ALL patients (114 B cell ALL (B-ALL) and 26 T cell ALL (T-ALL)) with matched germline and diagnostic samples
We found no correlation between the number of mutations and gender, age, and initial white blood cell (WBC) counts
Summary
Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. PAX5/ IKZF1 copy number abnormalities frequently exist in BALL, whereas mutations within NOTCH1, FBXW7, and CDKN2A/CDKN2B are enriched in T-ALL [1, 6,7,8]. The identification of these abnormalities reveals molecular pathology, and provides important therapeutic targets. Some targetable alterations or pathways have been used for therapeutic interventions in the clinic, especially kinaseactivating alterations in BCR-ABL1-positive or Philadelphia chromosome-like ALL patients who are amenable to tyrosine kinase inhibitors with improved survival rates [17, 18].
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