P2: Cancer Risk Assessment in Patients with Oral Premalignant Lesions

这项建议是建立在流行病学和分子遗传学的发现，从我们20年的经验， 口腔癌前病变（OPLs）的转化研究，口腔癌发展的标志。虽然 OPL的病因尚未完全清楚，这些病变通常与烟草和酒精有关 暴露;然而，目前尚不清楚为什么只有一小部分暴露于OPL的个体随后发展 口腔癌我们以前已经表明，具有某些遗传背景的OPL患者更多 易患口腔癌，以及OPL靶点中存在某些分子异常 组织预测这些病变的恶性转化率较高，与临床病理学无关。 参数这些预测标志物包括OPL组织学和OPL的组合生物标志物评分。 OPL中染色体多体性、p53蛋白表达和3 p和9 p杂合性缺失（洛） 组织中我们已经证明了一个成功的战略，全面的癌症风险评估OPL 通过结合传统的医学/人口统计学变量和一组生物标志物， 这些研究都使用了小样本量。我们建议通过利用最大的 OPL标本的可用资源，使我们有前所未有的机会研究350名患者 与OPL，前瞻性随访，平行我们的研究，遗传标记的替代品和目标， 组织，关键分子候选人，以及全球遗传畸变和表达谱，以确定 这些患者口腔癌风险的预测因素。利用这一独特的资源，我们将整合临床， 流行病学和遗传学数据，以建立口腔癌发展的定量风险评估模型。 我们的具体目标包括：1）评估替代组织（淋巴细胞）中的易感性标志物; 2）评估 全球基因组和转录组异常以及OPL靶点中的关键候选分子 组织;和3）对来自临床、流行病学、替代靶点的数据进行全面分析 组织、基因型-表型、全球候选生物标志物面板与患者的临床结果，以建立一个 口腔癌发展的风险评估模型。OPL患者亚组的确定 更高的口腔癌发展风险将允许开发个性化的，基于机制的 化学预防干预措施和更有效的筛查和治疗战略。

This proposal is built upon the epidemiologic and molecular genetic findings from our 20-year experience in translational research in oral premalignant lesions (OPLs), a hallmark of oral cancer development. Although the etiology of OPLs is not fully understood, these lesions are often associated with tobacco and alcohol exposures; however, it is unclear why only a fraction of exposed individuals with OPL subsequently develop oral cancer. We have previously shown that OPL patients with certain genetic backgrounds are more susceptible to developing oral cancer, and that certain molecular abnormalities that present in OPL target tissues predict a higher rate of malignant transformation of these lesions, independent of clinicopathologic parameters. These predictive markers include OPL histology and the combined biomarker scores of chromosomal polysomy, p53 protein expression, and loss of heterozygosity (LOH) at 3p and 9p in OPL tissues. We have demonstrated a successful strategy for comprehensive cancer risk assessment in OPL patients by combining conventional medical/demographic variables and a panel of biomarkers; however, all of these studies have utilized small sample sizes. We propose to extend our studies by utilizing the largest available resource of OPL specimens that allows us the unprecedented opportunity to study 350 patients with OPLs, prospectively followed, to parallel our investigation of genetic markers in surrogate and target tissues, critical molecular candidates, and global genetic aberrations and expression profiles to identify predictors of oral cancer risk in these patients. Using this unique resource, we will integrate clinical, epidemiologic, and genetic data to build a quantitative risk assessment model for oral cancer development. Our Specific Aims include: 1) Assess susceptibility markers in surrogate tissue (lymphocytes); 2) Assess global genomic and transcriptomic abnormalities as well as critical candidate molecules in OPL target tissues; and 3) Complete comprehensive analyses of data from clinical, epidemiologic, surrogate-target tissue, genotype-phenotype, global-candidate biomarker panels with patients' clinical outcomes to build a risk assessment model for oral cancer development. The identification of subgroups of OPL patients at higher risk for oral cancer development will allow the development of individually tailored, mechanism-based chemopreventive interventions and strategies for more effective screening and treatment.