Predictive Value of MicroRNAs in the Progression of Oral Leukoplakias

项目总结 口腔鳞状细胞癌(OSCC)是一个世界性难题。据估计，中国有3万人 美国每年都被诊断出患有口腔鳞癌。由于大多数口腔鳞状细胞癌发展为 从先兆病变，在先兆阶段的准确识别和管理可提供 降低口腔鳞癌发病率和死亡率的最大希望。白斑(白斑)是 口腔鳞癌最常见的前驱病变。口腔白斑恶变率的研究 是可变的，利率高达31.4%。没有可靠的机制来选择性地识别 哪些白斑会发生恶变。标准的临床实践依赖于 高度上皮异型增生的显微镜检测以确定哪些是白斑 要接受治疗。这种方法的问题是它没有考虑到 白斑在组织学上不发育异常且级别较低，但仍进展为癌症。它有 据报道，高达16%的非增生性白斑进展为口腔鳞癌。发展中 一种预测性临床模式，可以准确地识别临床上的进展性皮损 白血球病急需治疗。一旦确诊，这些病变可以接受适当的临床治疗。 管理和随访，从而阻止恶变并显著改善 临床结果。进行性白斑的早期发现和处理将 为根除口腔鳞状细胞癌作出重大贡献。拟议研究的目的是制定和实施 验证基于microRNA(MiR)标记的口腔癌进展预测模式。在 在研究的初始阶段，我们建议进行全基因组的miR表达评估 对10例非霍奇金淋巴瘤患者的切面活检组织标本进行下一代测序 5年无病生存的发育不良或低度发育不良口腔白斑(组 1)，相比之下，年龄和性别匹配的非发育不良或低级别患者为10人 5年内进展为口腔鳞癌的口腔白斑(第2组)。生物信息学分析将 用于整合测序数据以识别miR靶基因和miR介导的 致癌网络和致癌途径。最好的MIR候选对象，可以识别那些患有 选择敏感度和特异度高的进展性病变形成预后MIR 目标1中的标记面板。然后，将在目标2中的 另外40对第1组-第2组使用RT-qPCR。据我们所知，建议的 创新的方法从未被应用于预测口腔白斑的进展。这 建议提供了可扩展性和成本控制，同时允许采用不可知的方法 发现整个基因组中的分子变化，然后进行独立验证。

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is a worldwide problem. An estimated 30,000 people in the United States are diagnosed with OSCC each year. Since the majority of OSCC develop from precursor lesions, accurate identification and management at the precursor stage offers the best hope at reducing OSCC morbidity and mortality. Leukoplakias (white patches) are the most common precursor lesion of OSCC. The malignant transformation rate of oral leukoplakia is variable with rates as high as 31.4%. No reliable mechanism exists to selectively identify which leukoplakias will undergo malignant transformation. Standard clinical practice relies on the microscopic detection of high-grade epithelial dysplasia to dictate which leukoplakias are subject to treatment. The problem with this approach is that it fails to account for the subset of leukoplakias that are histologically nondysplastic and low grade yet progress to cancer. It has been reported that as high as 16% of nondyplastic leukoplakias progress to OSCC. Developing a predictive clinical modality that can accurately identify progressive lesions among clinical leukoplakias is in critical need. Once identified, these lesions can receive appropriate clinical management and follow-up, thereby halting malignant transformation and significantly improving the clinical outcome. Early detection and management of progressive leukoplakias will significantly contribute to eradication of OSCC. The aim of the proposed study is to develop and validate a microRNA (miR) marker-based predictive modality for oral cancer progression. In the initial phase of the study, we propose to perform a genome-wide miR expression assessment via next generation sequencing in 10 incisional biopsy tissue samples from patients with non dysplastic or low grade dysplastic oral leukoplakias who had 5 year disease-free survival (Group 1), compared with 10 from age- and gender- matched patients with non dysplastic or low grade oral leukoplakias that progressed to OSCC within 5 years (Group 2). Bioinformatics analysis will be performed to integrate sequencing data to identify miR target genes and miR-mediated oncogenic networks and pathways. Top miR candidates that can identify those patients with progressive lesions with high sensitivity and specificity will be selected to form a prognostic miR marker panel in Aim 1. The candidate marker panel will then be validated in Aim 2 in an additional 40 Group 1-Group 2 pairs using RT-qPCR. To our knowledge the proposed innovative approach has never been applied to predict progression of oral leukoplakias. This proposal offers scalability and cost containment while allowing an agnostic approach to discovery of molecular changes across the genome that is followed by independent validation.