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

摘要 口腔鳞状细胞癌(OCSCC)是一种致命性疾病，通常先于癌前病变。 病变，使其成为一种理想的疾病筛查举措。然而，目前的筛查方案/测试不能 可靠地区分炎性和癌前发育不良病变。此外，组织学诊断 不典型增生是恶变的不完全预测因素，因为只有约15%的口腔癌前病变 癌症的进展。我们的长期目标是建立基于分子的诊断测试，用于预测 以及能够识别最有可能进展为口腔癌的高危患者的筛查，但 从更密切的监测和较少病态的治疗意图程序中受益匪浅。我们的中心假设是 癌前病变包含可识别的基因突变，可用于可靠的活检预测 (组织活检)和筛查(唾液)。我们将确定异型增生特异性突变的潜在原因 口腔鳞癌的发病机制。我们将验证在一项回顾性病例队列研究中发现的突变 已知临床结果的发育不良口腔组织研究其作为组织学预后的可能性 生物标志物。我们将使用五个现有纵向人群的唾液样本进行病例队列研究- 总部设在美国的队列，以确定是否可以在唾液中发现司机体细胞突变 口腔癌的诊断。这些研究在概念上是创新的，可能会导致最先进的风险 分层筛选。他们将是第一个定义口腔功能驱动突变的人 癌症前疾病。他们也将是第一个确定是否可以在唾液中检测到司机基因突变的人 在口腔癌诊断前，确定突变检测的时间进程，并测试其预测能力 识别具有体细胞突变的高危个体。他们在技术上具有创新性，因为他们评估了 一种新的非侵入性分子唾液筛查平台的诊断准确性。这项研究将有益于 通过提高我们识别可能进展为癌症的高危癌前口腔病变的能力， 从而允许在发病率和死亡率有限的情况下进行更早和可能更有效的干预。

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.