Somatic Mutations in Tissue and Saliva as Prognostic and Screening Biomarkers for Oral Premalignancy

组织和唾液中的体细胞突变作为口腔癌前病变的预后和筛查生物标志物

• 批准号: 10189552
• 负责人: Nishant Agrawal
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10189552
• 关键词: Biological Markers; Biopsy; Categories; Clinical; Cohort Studies; Collection; Control Groups; Coupled; DNA Sequence Alteration; Detection; Devices; Diagnosis; Diagnostic tests; Disease; Dysplasia; Eligibility Determination; Genes; Goals; Gold; Head and Neck Squamous Cell Carcinoma; Health; Histologic; Human; Hyperplasia; Incidence; Individual; Inflammatory; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Methods; Modality; Molecular; Morbidity - disease rate; Mutation; Mutation Detection; Oral; Oral Diagnosis; Outcome; Pathogenesis; Patients; Procedures; Prognostic Marker; Research; Retrospective cohort; Saliva; Salivary; Severe dysplasia; Somatic Mutation; Tactile; Testing; Therapeutic; Time; Tissues; United States; Visual; Work; base; cancer diagnosis; cohort; curative treatments; diagnostic accuracy; driver mutation; high risk; improved; innovation; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; next generation sequencing; novel; oral dysplasia; oral lesion; oral premalignancy; oral tissue; population based; predictive test; premalignant; prognostic; prognostic assays; risk stratification; saliva sample; screening; targeted sequencing

ABSTRACT Oral cavity squamous cell carcinoma (OCSCC) can be a lethal disease that is often preceded by premalignant lesions, making it is an ideal disease for screening initiatives. However, current screening protocols/tests cannot reliably differentiate between inflammatory and premalignant dysplastic lesions. Further, the histologic diagnosis of dysplasia is an imperfect predictor of malignant transformation as only ~15% of premalignant oral lesions progress to cancer. Our long-term goals are to establish molecular-based diagnostic tests for prognostication and screening that are capable of identifying high-risk patients most likely to progress to oral cancer but would greatly benefit from closer surveillance and less morbid curative intent procedures. Our central hypothesis is that premalignant lesions contain identifiable genetic mutations that can be used for reliable biopsy prognostication (tissue biopsies) and screening (saliva). We will identify dysplasia-specific mutations underlying the pathogenesis of OCSCC. We will validate the mutations identified in a retrospective case-cohort study of dysplastic oral tissues with known clinical outcomes to investigate their potential as tissue-based prognostic biomarkers. We will conduct a case-cohort study using saliva samples from five existing longitudinal population- based United States cohorts to determine whether driver somatic mutations can be identified in saliva prior to the diagnosis of oral cancer. These studies are conceptually innovative and likely to result in state-of-the-art risk stratification and screening. They would be the first to define the functional driver mutations of oral premalignancy. They would also be the first to determine if mutations in driver genes can be detected in saliva prior to oral cancer diagnosis, to define the time-course of mutation detection, and to test the predictive ability of identifying high-risk individuals with somatic mutations. They are technically innovative, as they evaluate the diagnostic accuracy of a novel non-invasive molecular salivary screening platform. This research will benefit human health by improving our ability to identify high-risk premalignant oral lesions likely to progress to cancer, thereby allowing for earlier and potentially more curative interventions with limited morbidity and mortality.

抽象的 口腔鳞状细胞癌（OCSCC）可能是致命的疾病 病变，使其成为筛查计划的理想疾病。但是，当前的筛选协议/测试不能 可靠地区分炎症和前异型性病变。此外，组织学诊断 发育不良是恶性转化的不完善的预测指标 癌症的进展。我们的长期目标是为预后建立基于分子的诊断测试 和能够识别最有可能患上口腔癌的高危患者的筛查 仔细监测和病态的治疗意图程序较少受益。我们的中心假设是 前病变含有可识别的遗传突变，可用于可靠的活检预后 （组织活检）和筛查（唾液）。我们将确定其依据性突变的特异性突变 OCSCC的发病机理。我们将验证在回顾性病例研究中发现的突变 具有已知临床结局的发育不良口腔组织，以研究其潜力作为基于组织的预后 生物标志物。我们将使用来自五个现有纵向人群的唾液样本进行病例研究 总部位于美国同伙，以确定驾驶员在唾液中是否可以在唾液中识别 口腔癌的诊断。这些研究在概念上具有创新性，并且可能导致最新风险 分层和筛选。他们将是第一个定义口服功能驱动器突变的人 预先记录。他们也将是第一个确定在唾液中是否可以检测到驱动基因突变的人 在口腔癌诊断之前，定义了突变检测的时间顺序，并测试了预测能力 识别具有躯体突变的高风险个体。他们在技术上是创新的，因为他们评估了 新型非侵入性分子唾液筛查平台的诊断准确性。这项研究将受益 通过提高我们确定可能发展为癌症的高风险前口腔病变的能力，以提高人类健康， 从而允许较早，潜在的治疗性干预措施有限，发病率和死亡率有限。