二代分子测序在软组织肉瘤中的应用价值分析

Analysis of the application of next-generation sequencing in soft tissue sarcoma

    摘要
  • 摘要:
      目的  探索中国人群软组织肉瘤常见的基因变异；分析二代基因测序技术（next-generation sequencing，NGS）在软组织肉瘤诊疗中的价值。
      方法  本研究纳入北京大学肿瘤医院2018年1月至2020年12月接受NGS检测的软组织肉瘤（soft tissue sarcomas, STS）患者，分析基因变异的频率和分布特点；统计具有临床治疗意义的基因变异情况，包括符合美国国立综合癌症网络（NCCN）或中国临床肿瘤学会指南（CSCO）治疗建议、超适应证治疗药物，或正在招募中的针对特定变异的临床试验；探索STS的肿瘤突变负荷（tumor mutational burden，TMB）水平及微卫星不稳定（microsatellite instability，MSI）状态。
      结果  108例患者中有74例（68.5%）的基因变异数≥1。共发现78种不同的基因变异，变异频率排名前10位的基因包括TP53 12.3%（22/179）、MDM2 7.3%（13/179）、CDK4 5.6%（10/179）、CDKNB 3.9%（7/179），RB1 3.9%（7/179），ALK 2.8%（5/179），ATRX 2.8%（5/179），MCL1 2.8%（5/179），FGFR1 2.2%（4/179），PIK3CA 2.2%（4/179）。治疗获益方面，108例患者中有7例（6.5%）的突变基因符合指南治疗建议，31例（28.7%）具有超适应证治疗可能，56例（51.9%）可接受正在招募中的针对变异基因的STS临床试验，62例（57.4%）符合指南治疗建议或存在超适应证治疗可能或符合正在招募中的针对变异基因的STS临床实验。全组中位TMB值为2.42（0～60）muts/Mb，108例患者中有10例（9.3%）TMB值≥10 muts/Mb，24例（22.2%）TMB值5～10 muts/Mb，74例（68.5%）TMB值<5 muts/Mb。89例患者接受了MSI检测，仅1例患者为微卫星高度不稳定（MSI-H）（1.1%）。
      结论  软组织肉瘤常见的基因变异包括TP53、MDM2、CDK4、CDKNB和RB1。通过NGS检测获得符合指南治疗建议的比例较低，但获得超适应证用药和临床试验建议的比例较高。TMB值、MSI状态对STS患者的临床意义还需进一步证实。

     

    Abstract:
      Objective  To investigate common mutation genes of soft tissue sarcoma (STS) in the Chinese population and analyze the application of next-generation sequencing (NGS) in treating STS.
      Methods  The frequency and distribution of gene variations were analyzed in patients with STS who underwent NGS at Peking University Cancer Hospital & Institute from January 2018 to December 2020. The number of therapeutic variants was determined. The therapeutic variants included those that met the National Comprehensive Cancer Network (NCCN) or Chinese Society of Clinical Oncology (CSCO) guidelines, the existence of off-label treatment, and the ongoing recruitment of STS clinical trials with a gene variant. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also investigated.
      Results  Seventy-four of 108 patients (68.5%) had at least one genetic variation. A total of 78 different gene variants were found, and the top 10 gene variants included TP53 (22/179,12.3%), MDM2 (13/179,7.3%), CDK4 (10/179, 5.6%), CDKNB (7/179,3.9%), RB1 (7/179, 3.9%). ALK (5/179, 2.8%), ATRX (5/179, 2.8%), MCL1 (5/179, 2.8%), FGFR1 (4/179, 2.2%), and PIK3CA (4/179, 2.2%). Regarding therapeutic benefits, seven patients (6.5%) had genetic mutations that met the treatment guideline recommendations, 31 patients (28.7%) were administered possible off-label treatments, and 56 patients (51.9%) were enrolled in an STS clinical trial targeting the mutated genes. Sixty-two patients (57.4%) had the potential for off-label treatment or met the criteria for ongoing STS clinical trials targeting gene variants. The median TMB of the whole group was 2.42 (0–60) muts/Mb, and 10 patients (9.3%) had TMB ≥10 muts/Mb, 24 (22.2%) had TMB 5–10 muts/Mb, and 74 (68.5%) had TMB <5 muts/Mb. Only one patient (1.1%) had high MSI.
      Conclusions  The common gene variants of STS include TP53, MDM2, CDK4, CDKNB, and RB1. A very low proportion of patients were receiving treatments in line with guidelines based on NGS. However, high proportions of off-label drug use and clinical trial recommendations were noted. The clinical significance of TMB value and MSI status in patients with STS requires further confirmation.

     

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