Predictive Value of MicroRNAs in the Progression of Oral Leukoplakias

描述（由申请人提供）：口腔鳞状细胞癌（OSCC）是一个世界性的问题。据估计，美国每年有30，000人被诊断患有OSCC。由于大多数口腔鳞状细胞癌是由前驱病变发展而来，因此在前驱阶段进行准确的识别和治疗是降低口腔鳞状细胞癌发病率和死亡率的最大希望。白斑（白色斑）是口腔鳞状细胞癌最常见的前驱病变。口腔白斑恶变率高，高达31.4%。没有可靠的机制存在，以选择性地确定哪些白血病将进行恶性转化。标准的临床实践依赖于高度上皮异型增生的显微镜检测来决定哪种白斑症需要治疗。这种方法的问题在于，它不能解释组织学上非发育异常和低级别但进展为癌症的白血病的子集。据报道，高达16%的非增生性白斑发展为口腔鳞状细胞癌。开发一种预测性的临床模式，可以准确地识别临床白斑病中的进展性病变是迫切需要的。一旦发现，这些病变可以接受适当的临床管理和随访，从而阻止恶性转化并显著改善临床结局。进行性白斑病的早期发现和治疗将大大有助于口腔鳞癌的根除。该研究的目的是开发和验证一种基于microRNA（miR）标记的口腔癌进展预测模式。在研究的初始阶段，我们建议通过下一代测序在来自具有5年无病生存期的非发育不良或低度发育不良口腔白斑患者的10个切口活检组织样本中进行全基因组miR表达评估（组1），与之相比，年龄和性别匹配的10名非异型增生或低度口腔白斑病患者在5年内进展为口腔鳞状细胞癌（第2组）。将进行生物信息学分析以整合测序数据，从而鉴定miR靶基因和miR介导的致癌网络和途径。将选择能够以高灵敏度和特异性鉴定具有进行性病变的那些患者的最佳miR候选物以形成目标1中的预后miR标志物组。然后在目标2中使用RT-qPCR在另外40个组1-组2对中验证候选标记物组。据我们所知，所提出的创新方法从未被应用于预测口腔白斑的进展。该提案提供了可扩展性和成本控制，同时允许采用不可知的方法来发现整个基因组的分子变化，然后进行独立验证。

DESCRIPTION (provided by applicant): 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.