Supplementary Material for: Characteristics of molecular genetic mutations and their correlation with prognosis in adolescent and adult patients with ALL

Introduction: The prognosis of acute lymphoblastic leukemia (ALL) in adolescents and adults is poor, and recurrence is an important cause of their death. Changes of genetic information play a vital role in the pathogenesis and recurrence of ALL; however, the impact of molecular genetic mutations on disease diagnosis and prognosis remains unexplored. This study aimed to explore the frequency spectrum of gene mutations and their prognostic significance, along with the minimal residual disease (MRD) level and hematopoietic stem cell transplantation (HSCT), in adolescent and adult patients aged ≥15 years with ALL. Methods: The basic characteristics, cytogenetics, molecular genetics, MRD level, treatment regimen and survival outcome of patients with untreated ALL (≥15 years) were collected, and the correlation and survival analysis were performed using the SPSS 25.0 and R software. Results: This study included 404 patients, of which 147 were selected for next-generation sequencing (NGS). NGS results revealed that 91.2 % of the patients had at least one mutation, and 67.35% had multiple (≥ 2) mutations. NOTCH1, PHF6, RUNX1, PTEN, JAK3, TET2, and JAK1 were the most common mutations in T-ALL, whereas FAT1, TET2, NARS, KMT2D, FLT3, and RELN were the most common mutations in B-ALL. Correlation analysis revealed the mutation patterns, which were significantly different between T-ALL and B-ALL. In the prognostic analysis of 107 patients with B-ALL, multivariate analysis showed that the number of mutations ≥5 was an independent risk factor for overall survival and the RELN mutation was an independent poor prognostic factor for event-free survival. Discussion: The distribution of gene mutations and the co-occurrence and repulsion of mutant genes in patients with ALL were closely related to the immunophenotype of the patients. The number of mutations ≥5 and the RELN mutation were significantly associated with poor prognosis in adolescent and adult patients with ALL.

研究背景：青少年及成人急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）预后较差，复发是其主要死亡原因。遗传信息改变在ALL的发病机制与复发过程中发挥关键作用，但分子遗传突变对疾病诊断及预后的影响仍有待阐明。本研究旨在探究15岁及以上青少年与成人ALL患者的基因突变频谱及其预后意义，同时分析微小残留病（minimal residual disease, MRD）水平与造血干细胞移植（hematopoietic stem cell transplantation, HSCT）的相关作用。
研究方法：收集未经治疗的15岁及以上ALL患者的基线特征、细胞遗传学、分子遗传学、MRD水平、治疗方案及生存结局数据，采用SPSS 25.0与R软件进行相关性分析与生存分析。
研究结果：本研究共纳入404例患者，其中147例接受下一代测序（next-generation sequencing, NGS）检测。NGS结果显示，91.2%的患者至少存在1处基因突变，67.35%的患者存在多处（≥2处）基因突变。T细胞型ALL（T-ALL）最常见的突变为NOTCH1、PHF6、RUNX1、PTEN、JAK3、TET2及JAK1；B细胞型ALL（B-ALL）最常见的突变为FAT1、TET2、NARS、KMT2D、FLT3及RELN。相关性分析显示，T-ALL与B-ALL的基因突变模式存在显著差异。对107例B-ALL患者的预后分析中，多因素分析结果表明，基因突变数≥5是总生存期的独立危险因素，而RELN突变是无事件生存期的独立不良预后因素。
讨论：ALL患者的基因突变分布、突变基因的共现与互斥现象与患者的免疫表型密切相关。基因突变数≥5及RELN突变与青少年及成人ALL患者的不良预后显著相关。