Development of a Four-Class, Molecular Subtyping Diagnostic for HPV-negative Head and Neck Cancer

摘要： 头颈部鳞状细胞癌（HNSCC），包括口腔癌、咽癌和 喉癌是全球第六大常见癌症。在美国，大约有6万人 预计2015年将出现HNSCC新病例和12，000例死亡。越来越多的证据表明 口咽癌发病率增加，包括人乳头瘤病毒（HPV）亚型 相关的肿瘤，表现出更好的预后。尽管最近对HPV阳性的研究兴趣 HNSCC中，HPV阴性烟草相关病例继续构成绝大多数HNSCC。 特别是在我们的北卡罗来纳州，那里的人口在种族和社会经济方面都更加多样化。 在烟草使用仍然很高的地方，HPV阴性的HNSCC仍然是一个重要的公共卫生问题。 问题. HPV阴性HNSCC的肿瘤学结局仍然很差，在过去的50年中没有改善。 多年来，需要为患者确定新颖的个性化诊断和治疗策略 HPV阴性的HNSCC四种内源性HNSCC基因表达亚型（基础（BA），经典（CL）， 间充质（MS）和非典型（AT）），并提供了一个机会，告知患者 管理这些亚型在细胞起源、肿瘤驱动、增殖 预后和宿主免疫应答。在此应用中，我们打算开发和验证一个临床就绪的 HPV阴性HNSCC的诊断，包括预后和预测应用。而 对于HNSCC存在几种治疗选择，包括手术、放射治疗和化疗， 治疗选择仍然是经验性的。除了口咽癌中的HPV状态外， 在决定是否治疗时，通常不考虑单个肿瘤的分子特征。 治疗这种学术/工业合作将提供基于生物基因的预后信息 表达亚型，以指导HPV阴性HNSCC的决策，如应用更多的 基于肿瘤特征的侵袭性手术或放射治疗。我们假设发展 本申请中所述的努力将导致临床准备好的亚型诊断， 其他突变和临床数据，将提供预后和预测应用，以指导 HNSCC的管理。

Abstract: Head and neck squamous cell carcinoma (HNSCC), including cancers of the oral cavity, pharynx, and larynx, is the sixth most common cancer worldwide worldwide. In the United States, approximately 60,000 new cases of HNSCC and 12,000 deaths are projected for 2015. A growing body of evidence demonstrates increasing incidence of oropharyngeal cancers, including a subset of human papillomavirus (HPV) associated tumors that demonstrate better prognosis. Despite the recent research interest in HPV-positive HNSCC, HPV-negative tobacco-associated cases continue to comprise the vast majority of HNSCC. Particularly in our state of North Carolina, where the population is more racially and socioeconomically diverse and where tobacco use remains high, HPV-negative HNSCC remains a significant public health problem. Oncologic outcomes for HPV-negative HNSCC remain poor and have not improved in the last 50 years, and there is a need to identify novel, personalized diagnostics and treatment strategies for patients with HPV-negative HNSCC. Four intrinsic HNSCC gene expression subtypes (basal (BA), classical (CL), mesenchymal (MS) and atypical (AT)) have been described, and provide an opportunity to inform patient management. These subtypes exhibit distinct differences in cell of origin, tumor drivers, proliferation, prognosis, and host immune response. In this application, we intend to develop and validate a clinic-ready diagnostic for HPV-negative HNSCC that includes both prognostic and predictive applications. While several therapeutic options exist for HNSCC including surgery, radiation therapy, and, chemotherapy, treatment selection remains empiric. With the exception of HPV status in oropharyngeal cancer, the molecular characteristics of individual tumors are generally not taken into account when deciding on treatment. This academic/industry collaboration will provide prognostic information based on biologic gene expression subtypes to guide decision-making for HPV-negative HNSCC, such as application of more aggressive surgery or radiation therapy based on tumor characteristics. We hypothesize that development efforts as described in this application will lead to a clinic-ready subtyping diagnostic, that combined with other mutation and clinical data, will provide both prognostic and predictive applications to guide the management of HNSCC.