Fan Wen-Lang, Yang Lan-Yan, Hsieh Jason Chia-Hsun, Lin Tsung-Chieh, Lu Mei-Yeh Jade, Liao Chun-Ta
Genomic Medicine Core Laboratory, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan.
Clinical Trial Center, Biostatistics and Informatics Unit, Linkou Chang Gung Memorial Hospital, Taoyuan 33382, Taiwan.
Cancers (Basel). 2021 May 30;13(11):2709. doi: 10.3390/cancers13112709.
Mutational profiling of patients' tumors has suggested that the development of oral cavity squamous cell carcinoma (OCSCC) is driven by multiple genes in multiple pathways. This study aimed to examine the association between genomic alterations and clinical outcomes in patients with advanced stages OCSCC to facilitate prognostic stratification. We re-analyzed our previous whole-exome sequencing data from 165 long-term follow-ups of stages III and IV patients with OCSCC. Their frequent mutations were mapped to 10 oncogenic signaling pathways. Clinicopathological risk factors, relapse, and survival were analyzed to identify the genetic factors associated with advanced OCSCC. Frequent genetic alterations included point mutations in TP53, FAT1, NOTCH1, CASP8, CDKN2A, HRAS, PIK3CA, KMT2B (also known as MLL4), and LINC00273; amplified segments in CCND1, EGFR, CTTN, and FGFR1; and lost segments in CDKN2A, ADAM3A, and CFHR1/CFHR4. Comprehensive analysis of genetic alterations revealed that subgroups based on mutational signatures had a significant negative impact on disease-free survival ( = 0.0005) and overall survival ( = 0.0024). Several important signaling pathways were identified to be frequently genetically altered in our cohort. A specific subgroup of patients with alterations in NOTCH, RTK/RAS/MAPK, and TGF-beta pathways that had a significantly negative impact on disease-free survival ( = 0.0009). Thirty percent of samples had multiple targetable mutations in multiple pathways, indicating opportunities for novel therapy.
对患者肿瘤的突变分析表明，口腔鳞状细胞癌（OCSCC）的发生是由多个途径中的多个基因驱动的。本研究旨在探讨晚期OCSCC患者基因组改变与临床结局之间的关联，以促进预后分层。我们重新分析了之前对165例III期和IV期OCSCC患者进行长期随访的全外显子测序数据。将他们频繁发生的突变映射到10条致癌信号通路。分析临床病理危险因素、复发和生存情况，以确定与晚期OCSCC相关的遗传因素。常见的基因改变包括TP53、FAT1、NOTCH1、CASP8、CDKN2A、HRAS、PIK3CA、KMT2B（也称为MLL4）和LINC00273中的点突变；CCND1、EGFR、CTTN和FGFR1中的扩增片段；以及CDKN2A、ADAM3A和CFHR1/CFHR4中的缺失片段。对基因改变的综合分析显示，基于突变特征的亚组对无病生存期（=0.0005）和总生存期（=0.0024）有显著负面影响。在我们的队列中，确定了几条重要的信号通路经常发生基因改变。NOTCH、RTK/RAS/MAPK和TGF-β通路发生改变的特定患者亚组对无病生存期有显著负面影响（=0.0009）。30%的样本在多个途径中有多个可靶向突变，这表明有新的治疗机会。
