Department of Medical Research, MacKay Memorial Hospital No. 92, Sec. 2, Chung San N. Rd., Taipei 10449, Taiwan.
Institute of Oral Biology, School of Dentistry, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
Int J Mol Sci. 2023 Jun 20;24(12):10408. doi: 10.3390/ijms241210408.
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 , , , and were most frequently mutated in OSCC, and known driver genes, including , , and , were also significantly and frequently mutated. Additionally, the novel mutated genes , , and were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were , , and 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.
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，尤其是无细胞 DNA（cfDNA）分析，是一种用于基因组分析的微创技术。我们使用多种突变calling 管道和过滤标准，对 50 对 OSCC 无细胞血浆与全血样本进行了全面的外显子组测序（WES）。使用 Integrative Genomics Viewer（IGV）验证体细胞突变。突变负担和突变基因与临床病理参数相关。cfDNA 的血浆突变负担与临床分期和远处转移状态显著相关。在 OSCC 中，最常突变的基因包括、、、和，已知的驱动基因，包括、、和，也显著且频繁突变。此外，在 OSCC 患者中还存在显著且频繁出现的新型突变基因、和。在转移性 OSCC 患者中最常发现的突变基因是、和。进一步分析显示，支链氨基酸（BCAA）分解代谢、细胞外基质-受体相互作用和缺氧相关途径与 OSCC 预后相关。癌症中的胆碱代谢、O-聚糖生物合成和内质网途径中的蛋白质加工与远处转移状态相关。约 20%的肿瘤携带至少一个 BCAA 分解代谢信号异常事件，可能可以通过已批准的治疗药物靶向治疗。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 血浆基因组中主要改变事件的景观。这些发现将有助于设计针对 OSCC 的靶向治疗临床试验，并根据治疗效果对患者进行分层。
