口腔鳞状细胞癌(OSCC)的准确诊断和治疗需要了解其基因组改变。液体活检,特别是无细胞DNA(cfDNA)分析,是一种用于基因组分析的微创技术。我们使用多个突变识别管道和过滤标准对50对OSCC无细胞血浆和全血样品进行了全面的全外显子组测序(WES)。整合基因组学查看器(IGV)用于验证体细胞突变。突变负荷和突变基因与临床病理参数相关。cfDNA的血浆突变负荷与临床分期和远处转移状态显着相关。TTN基因,PLEC,SYNE1和USH2A在OSCC中最常见的突变,和已知的驱动基因,包括KMT2D,LRP1B,TRRAP,还有FLNA,也显著和频繁地突变。此外,新突变基因CCDC168,HMCN2,STARD9和CRAMP1在OSCC患者中显著且频繁存在.在转移性OSCC患者中最常见的突变基因是RORC,SLC49A3和NUMBL。进一步的分析表明,支链氨基酸(BCAA)分解代谢,细胞外基质-受体相互作用,缺氧相关通路与OSCC预后相关。癌症中的胆碱代谢,O-聚糖生物合成,内质网途径的蛋白质处理与远处转移状态有关。约20%的肿瘤在BCAA分解代谢信号传导中携带至少一个异常事件,其可能被批准的治疗剂靶向。我们确定了与病因和预后相关的分子水平OSCC,同时定义了OSCC血浆基因组的主要改变事件的景观。这些发现将有助于设计靶向治疗的临床试验以及根据治疗效果对OSCC患者进行分层。
The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genes TTN, PLEC, SYNE1, and USH2A were most frequently mutated in OSCC, and known driver genes, including KMT2D, LRP1B, TRRAP, and FLNA, were also significantly and frequently mutated. Additionally, the novel mutated genes CCDC168, HMCN2, STARD9, and CRAMP1 were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were RORC, SLC49A3, and NUMBL. Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix-receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy.