Background:Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling.Methods:A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set atp< 0.05.Results:Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2,PBRM1,ARID1A). Mutations were also common among theTERTpromoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified amongPBRM1,BRCA2, andKMT2Dmutations.CDKN2A/Bdeletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults.Conclusions:This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.
背景：脊索瘤是一种起源于胚胎脊索残余的罕见原发性肿瘤，由于对其基因组特征了解有限，系统性治疗选择受限。本研究旨在利用美国癌症研究协会GENIE项目这一大型国家级患者层面基因组数据库，系统分析脊索瘤的遗传学改变，以识别潜在治疗靶点并改进疾病模型构建。 方法：基于AACR Project GENIE数据库对脊索瘤样本进行回顾性分析。通过靶向测序数据分析复发性体细胞突变、肿瘤突变负荷及染色体拷贝数变异，显著性阈值设定为p<0.05。 结果：研究发现影响染色质重塑的SWI/SNF复合体相关基因（SETD2、PBRM1、ARID1A）存在高频突变。TERT启动子区域及细胞周期调控基因CDKN2A亦常见突变。PBRM1、BRCA2和KMT2D突变之间存在显著共现现象。CDKN2A/B缺失在转移性肿瘤中富集，儿童病例与成人患者相比呈现独特的突变谱。 结论：本研究系统描绘了脊索瘤的基因组特征图谱，识别出关键突变位点及潜在治疗靶点。这些发现揭示了染色质重塑和细胞周期通路在脊索瘤生物学中的重要作用，为未来精准医疗策略和治疗干预提供了新的见解。
Genomic Characterization of Chordoma: Insights from the AACR Project GENIE Database
肿瘤(癌症)患者之家