Honghong Zhang1,2, Hongsheng Wang1,2, Xiaowen Qian1,2, Shuai Gao2, Jieqi Xia2, Junwen Liu2, Yanqin Cheng1,2, Jie Man1,2, Xiaowen Zhai3,4. 1. Department of Hematology oncology, Children's hospital of Fudan university, 399 Wanyuan Road, Shanghai, China. 2. Clinical laboratory center, Children's hospital of Fudan University, Shanghai, China. 3. Department of Hematology oncology, Children's hospital of Fudan university, 399 Wanyuan Road, Shanghai, China. zhaixiaowendy@163.com. 4. Clinical laboratory center, Children's hospital of Fudan University, Shanghai, China. zhaixiaowendy@163.com.
Abstract
BACKGROUND: 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. However, the genetic mechanisms that give rise to ALL remain poorly understood. METHODS: Using 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. RESULTS: Our 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. CONCLUSION: Overall, 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.
BACKGROUND: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. However, the genetic mechanisms that give rise to ALL remain poorly understood. METHODS: Using 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. RESULTS: Our 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. CONCLUSION: Overall, 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.
Authors: Sarah Meyers; Llucia Alberti-Servera; Olga Gielen; Margot Erard; Toon Swings; Jolien De Bie; Lucienne Michaux; Barbara Dewaele; Nancy Boeckx; Anne Uyttebroeck; Kim De Keersmaecker; Johan Maertens; Heidi Segers; Jan Cools; Sofie Demeyer Journal: Hemasphere Date: 2022-03-10
Authors: Hua Yin; Mei Hong; Jun Deng; Lan Yao; Chenjing Qian; Yao Teng; Tingting Li; Qiuling Wu Journal: Front Oncol Date: 2022-02-24 Impact factor: 6.244