Precision DNA methylation test to reduce oral cancer disparities in African Americans patients residing in low-resource settings

项目摘要 头颈部鳞状细胞癌(HNSCC)的诊断包括许多癌症亚型。我们会 重点介绍口腔鳞状细胞癌(OSCC)亚型上的建议项目。OSCC是第11个 世界上最常见的恶性肿瘤。尽管治疗取得了进展，但口腔鳞癌的5年存活率 在过去的25年里没有改善。口腔鳞状细胞癌是一种侵袭性很强的肿瘤，大多数患者 在诊断时显示为局部晚期疾病，需要综合治疗。肿瘤 侵袭、淋巴结转移和高区域复发率，除发生第二次外 原发肿瘤是口腔鳞癌患者的主要死亡原因。至少50%的局部感染患者 晚期口腔鳞状细胞癌出现局部区域或远处复发，通常发生在 治疗完成。在高质量医院的治疗与改善患者的存活率有关 OSCC。然而，与之相比，非洲裔美国人患者更不可能在高质量的医院接受治疗 美国的非拉丁裔白人患者，以及世界各地的贫穷患者。全球大多数HNSCC病例都是 在癌症后期被发现，因为不定期进行筛查，导致在 基于乡村、种族和性别的诊断，可以通过有针对性的筛查来减少。OSCC是 在世界范围内存在着最明显差异的肿瘤。发病率的巨大差异 高收入国家和低收入国家之间的差距主要是由于获得有效筛查和预先检查的机会不同。 癌症，或预防性治疗。类似的差距也存在于发达国家，如美国 口腔鳞状细胞癌的负担在低收入人群中最高。口腔鳞癌分子筛查应纳入 成人牙科就诊，因为口腔鳞状细胞癌的早期发现与更好的生存相关。的发展。 口腔鳞状细胞癌是一个多步骤的过程，需要积累多种DNA改变，受患者的 遗传易感性以及环境影响，包括烟草、酒精、慢性 炎症和感染人乳头瘤病毒。DNA改变主要由两种类型组成： 肿瘤抑制基因的变化，在失活时促进肿瘤的发展；以及 癌基因，在激活时会促进肿瘤的发展。肿瘤抑制基因可以失活 通过遗传事件或通过表观遗传修饰，如DNA甲基化。基因异常沉默 DNA甲基化是肿瘤发生发展过程中一个重要的表观遗传学事件，具有重要的生物学意义。 有可能成为早期诊断、肿瘤分子亚型、预后、监测和治疗的生物标记物。在……里面 这个Fast Track SBIR项目，我们建议演示一种精密的商业化可行性 DNA甲基化测试，即OralMethDx测试，用于对口腔鳞癌高危患者进行分层。我们的商业计划是 评估OralMethDx测试的两个独立适应症的性能：唾液风险测试 筛查和早期检测中的分层；以及用于诊断和预测的组织活检试验。

Project Summary A diagnosis of Head and neck squamous cell carcinoma (HNSCC) includes many cancer subtypes. We will focus on the oral cavity squamous cell carcinoma (OSCC) subtype on the proposed project. OSCC is the 11th most common malignancy in the world. Despite advances in treatments, the 5-year survival rates for OSCC have not improved for the past 25 years. OSCC is a very aggressive tumor, and the majority of patients displays a locoregionally advanced disease at diagnosis, for which multimodality therapy is required. Tumor invasion, lymph node metastasis and high rates of locoregional recurrence, besides development of second primary tumors, are the leading causes of death for OSCC patients. At least 50% of patients with locally advanced OSCC develop locoregional or distant relapses, which usually occur within the first 2 years of treatment completion. Treatment in high-quality hospitals is associated with improved survival for patients with OSCC. However, African American patients are less likely to be treated in high-quality hospitals compared with non-Latino white patients in US, as well as poor patients worldwide. Most HNSCC cases worldwide are detected at later stage of cancer because screening is not routinely conducted, leading to disparities at diagnosis based on rurality, race, and gender, which can be reduced by targeted screening. OSCC is one of the tumors in which the most glaring disparities exist worldwide. The dramatic disparity in incidence rates between high- and low-income countries is due primarily to differential access to effective screening and pre- cancer, or preventive, treatment. Similar disparities also exist within developed countries like the US where the burden of OSCC is highest in low-income populations. OSCC molecular screening should be included in dental visits for adults because early detection of OSCC is associated with better survival. The development of OSCC is a multistep process requiring the accumulation of multiple DNA alterations, influenced by a patient's genetic predisposition as well as by environmental influences, including tobacco, alcohol, chronic inflammation, and infection with Human Papilloma Virus. DNA alterations consist of two major types: alterations in tumor suppressor genes, which promote tumor development when inactivated; and alterations in oncogenes, which promote tumor development when activated. Tumor suppressor genes can be inactivated through genetic events or by epigenetic modifications such as DNA methylation. Gene silencing by aberrant DNA methylation is an important epigenetic event in cancer development and progression, which has great potential as a biomarker for early diagnosis, tumor molecular subtyping, prognosis, monitoring, and therapy. In this Fast Track SBIR project, we propose to demonstrate the feasibility for the commercialization of a precision DNA methylation test, the OralMethDx Test, to stratify patients at high risk of OSCC. Our business plan is to evaluate the performance of the OralMethDx Test for two separate indications: A saliva test for risk stratification in screening and early detection; and tissue biopsy test for diagnosis and prognostication.