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Gene 770 (2021) 145344

Contents lists available at ScienceDirect

Gene journal homepage: www.elsevier.com/locate/gene

Research paper

Comparison of gene mutation spectra in younger and older Chinese acute myeloid leukemia patients and its prognostic value Wei-jie Zhong a, Xiu-dan Liu b, Li-ye Zhong c, Kang-bao Li a, Qi-xin Sun a, Xin Xu a, Ting Wei d , Qing-shan Li d, Zhi-gang Zhu a, * a Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China b Department of Medical Ultrasound, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China c Department of Hematology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China d Department of Hematology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China

A R T I C L E I N F O

A B S T R A C T

Keywords: Acute myeloid leukemia SRSF2 Gene mutation Next-generation sequencing Older patients

Differences in the gene mutation spectra of younger and older Chinese adult AML patients and the prognostic significance of these differentially presented gene mutations are rarely reported. One hundred and thirteen newly diagnosed Chinese adults with AML, divided into groups of younger and older patients, were enrolled in this study. Bone marrow samples from the patients were analyzed using targeted next-generation sequencing with a panel of 141 genes. Ninety-eight mutated genes were detected and the top 10 mutated genes were KMT2D, FLT3, FAT1, ASXL1, NRAS, DNMT3A, RELN, TET2, JAK2, and KRAS. The top five functional groups were the tyrosine kinase pathway, transcription factors, DNA methylation, chromatin modifiers, and the JAK-STAT signaling pathway. Younger patients exhibited higher incidences of KMT2D (33.8% vs 10.4%, P = 0.004) and KRAS (15.4% vs 2.1%, P = 0.042) mutations than older patients; whereas, older patients harbored more SRSF2 (20.8% vs 0%, P = 0.002), transcription factor (85.4% vs 67.7%, P = 0.031), DNA methylation (58.3% vs 36.9%, P = 0.024), and RNA splicing (31.3% vs 12.3%, P = 0.013) mutations than younger patients. Moreover, patients with SRSF2 mutations exhibited a lower rate of overall survival (P < 0.001) and relapse-free survival (P < 0.001) than patients carrying wild-type SRSF2. In conclusion, rarely reported KMT2D, FAT1, and RELN mutations were detected at high frequencies in our cohort. The gene mutation spectrum of older patients was different to that of younger patients. Moreover, older patients harbored more SRSF2 mutations, which predicted lower rates of overall and relapse-free survival.

1. Introduction Acute myeloid leukemia (AML) is a heterogenous clonal malignancy characterized by the uncontrolled expansion of myeloid blasts in the bone marrow, peripheral blood, or other tissues. The incidence of AML increases in elderly patients, with a median age at diagnosis of 65–70 years (Siegel et al., 2019; SEER cancer statistics review). Although standard chemotherapy regimens, including cytarabine and daunorubicin or idarubicin, have improved clinical curative effects in younger patients, the prognosis for older patients remains poor (Longo et al.,

2015). In addition to a patient’s general physiological factors and chromosome abnormalities, the prognostic value of gene mutations in AML has become well accepted (Longo et al., 2015; Bullinger et al., 2017). Over the past 15 years, advances in microarray and next-generation sequencing (NGS) have significantly increased our knowledge of the genomic landscape in AML. As many studies have proven a prognostic role for molecular abnormalities in AML, some gene mutations such as those of FLT3-ITD and NPM1 have been incorporated into the latest adult AML risk stratification system (D¨ ohner et al., 2017; Metzeler et al.,

Abbreviations: AML, acute myeloid leukemia; DLBCL, diffuse large B cell lymphoma; FAB, French-American-British; NGS, next-generation sequencing; OS, overall survival; RFS, relapse-free survival. * Corresponding author at: Department of Geriatrics, Hematology & Oncology Ward, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Panfu Rd No.1, Yuexiu District, Guangzhou, Guangdong 510180, China. E-mail address: [email protected] (Z.-g. Zhu). https://doi.org/10.1016/j.gene.2020.145344 Received 28 July 2020; Received in revised form 1 November 2020; Accepted 1 December 2020 Available online 14 December 2020 0378-1119/© 2020 Elsevier B.V. All rights reserved.

W.-j. Zhong et al.

Gene 770 (2021) 145344

Hospital, Chinese Academy of Medical Sciences (Tianjin, China). The NGS library was prepared using at least 200 ng of genomic DNA. Sequencing was carried out on an Ion Proton System (Thermo Fisher Scientific, Waltham, MA, USA). The average read depth was 2,000×, with, on average, 5% of the target sequence being covered sufficiently deeply for variant calling. Samtools mpileup was used for single nucleotide variant/small insertions or deletions calling and the filter workflow. The FLT3-ITD mutation was verified by PCR and the NPM1-Exon12 mutation was verified by Sanger sequencing.

2016). In 2017, mutations of RUNX1 and ASXL1 were added into the European LeukemiaNet prognostic model for AML (D¨ ohner et al., 2017). Recently, however, data regarding molecular mutations in AML have been derived mainly from younger patients (D¨ ohner et al., 2017; Metzeler et al., 2016; Papaemmanuil et al., 2016). Previous research has demonstrated that the gene mutation spectrum of older patients differs ohner et al., 2017; Metzeler et al., 2016; from that of younger patients (D¨ Prassek et al., 2018). Reports on differences in the gene mutation landscapes of younger and older Chinese adult AML patients are limited, and the prognostic significance of these differentially presented gene mutations is rarely reported. In this study, we conducted targeted NGS with a panel of 141 genes in 113 Chinese adult AML patients aged 18–89 years. We aimed to investigate differences in the clinical characteristics and gene mutation spectra of younger and older patients, to identify gene mutations that were differentially mutated between younger and older patients, and to analyze survival rates in patients who did or did not carry the differentially expressed gene mutations.

2.4. Statistical analysis The overall survival (OS) period was defined as the time interval between the date of diagnosis to the date of death. The relapse-free survival (RFS) period for patients who had experienced complete remission was calculated as the time interval between the date of complete response and the date of relapse. The median (range) was used to describe continuous variables with non-normal distribution. The means of two continuous variables with normal distribution were compared by independent samples Student’s ttests. Non-normal variables were compared using non-parametric tests and chi-squared tests were used to analyze four-fold table data. Survival was analyzed using the Kaplan-Meier log-rank test. All statistical analyses were carried out using SPSS 21.0 software and P values of...