Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers
Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers
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DOI：
10.3233/blc-190251
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发表时间：
2019-01-01
期刊：
影响因子：
1.1
通讯作者：
Ward, Douglas G.
中科院分区：
文献类型：
--
作者：
Jeeta, Ruhana R.;Gordon, Naheema S.;Ward, Douglas G.
背景与目的：全基因组测序已经发现了可能在肿瘤发生中起重要作用的复发性非编码突变。我们调查了5个这样的非编码突变热点在尿路上皮膀胱癌（UBC）的频率，并评估其潜在的UBC检测和presticationation.METHODS：从302 UBC提取的DNA进行了有针对性的下一代测序的非编码突变热点GPR 126，PLEKHS 1，TBC 1D 12，LEPROTL 1和WDR 74。采用卡方检验、逻辑回归和考克斯比例风险模型分析突变频率以及与分期、分级、年龄、性别、吸烟状况、临床结局、突变特征和基因表达的关系。其中GPR 126占53.0%，PLEKHS 1占38.7%，TBC 1D 12占25.5%，LEPROTL 1占23.8%，WDR 74占17.2%。每个UBC平均有1.6个突变，74%的UBC至少有一个突变。它们经常共同出现，并且通常伴随APOBEC突变签名。这些突变与临床参数没有很强的相关性，并且很可能是UBC发展的早期事件。结论：这5个非编码热点突变在UBC中很常见。由于它们在疾病的各个阶段和等级中的频率很高，因此应将其纳入UBC诊断生物标志物组中。
BACKGROUND & OBJECTIVE: Whole genome sequencing has identified recurrent non-coding mutations that may be important in carcinogenesis. We investigate the frequency of 5 such non-coding mutation hotspots in urothelial bladder cancers (UBCs) and assess their potential for UBC detection and prognostication.METHODS: DNA extracted from 302 UBCs was subjected to targeted next generation sequencing of non-coding mutation hotspots in GPR126, PLEKHS1, TBC1D12, LEPROTL1 and WDR74. The frequency of mutations, and associations with stage, grade, age, gender, smoking status, clinical outcomes, mutation signatures and gene expression were analysed using chi(2) tests, logistic regression and Cox proportional hazards models.RESULTS: Non-coding mutations were common across all stages and grades of UBC. The frequencies were: GPR126 53.0%, PLEKHS1 38.7%, TBC1D12 25.5%, LEPROTL1 23.8% and WDR74 17.2%. There was an average of 1.6 mutations per UBC, and 74% of UBCs harboured at least one mutation. They frequently co-occur, and commonly accompany an APOBEC mutational signature. The mutations are not strongly associated with clinical parameters and are, most likely, early events in the development of UBC.CONCLUSIONS: Mutations at these 5 non-coding hotspots are common in UBC. Due to their high frequency across stages and grades of disease, they should be included in UBC diagnostic biomarker panels.