FFPE Validation of a Survival Gene Signature in HPV-Negative Oral Cavity Cancer

HPV 阴性口腔癌生存基因特征的 FFPE 验证

• 批准号: 9197967
• 负责人: CHU CHEN
• 金额: $ 61.2万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197967
• 关键词: Adjuvant; American Joint Committee on Cancer; Biological Assay; Breast; Canada; Cancer Center; Cancer Patient; Cessation of life; Characteristics; Clinical; Colon; DNA; Data Set; Diagnostic; Disease; Formalin; France; Fred Hutchinson Cancer Research Center; Freezing; Gene Chips; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Head and Neck Cancer; Hospitals; Human Papillomavirus; International Agency for Research on Cancer; Lead; Lung; Malignant Neoplasms; Michigan; Modality; Modeling; Molecular; Mouth Neoplasms; Multi-Institutional Clinical Trial; Operative Surgical Procedures; Oral Stage; Oral cavity; Oropharyngeal; Pain; Paraffin Embedding; Participant; Patient Care; Patients; Phase; Physicians; Prognostic Marker; Radiation; Radiosurgery; Running; Sampling; Staging; Technology; Testing; Time; Training; Tumor Tissue; Tumor stage; Utah; Validation; Washington; Work; base; chemotherapy; clinical Diagnosis; clinical care; clinical practice; cohort; cost effective; genetic signature; global health; improved; malignant breast neoplasm; malignant mouth neoplasm; malignant oropharynx neoplasm; molecular marker; mouth squamous cell carcinoma; nano-string; novel; orofacial; outcome forecast; personalized management; personalized medicine; prognostic; prospective; public health relevance; research clinical testing; survival outcome; survival prediction; treatment choice; tumor

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the oral cavity and oropharynx (OSCC) is a substantial global health burden, with an estimate of 529,000 new cases and over 292,000 deaths in 2012. OSCC can be further subclassified into entities with a different prognosis. For example, patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) tend to have better survival than those with HPV-negative OPC. However, prognostication for oral cavity cancer, which comprises the majority of OSCC and is mostly HPV-negative, is largely based on clinical staging, and molecular markers that could be used in clinical practice have not been identified. There is an urgent need to develop better prognostic markers for personalized clinical management of these patients. Our long-term goal is to develop simple, reliable, and cost-effective gene expression signatures to guide the management of OSCC patients. In our prior work (the Oralchip study, 5 R01 CA095419, PI: Chu Chen), we have identified a prognostic gene expression signature in tumor tissue that showed a greater ability than tumor stage to predict OSCC-specific survival for patients with HPV-negative OSCC, irrespective of types of treatment. We validated this signature using an independent set of patients with oral cavity cancer from the MD Anderson Cancer Center. This was the first demonstration of a gene expression signature that provides prognostic information beyond AJCC stage for oral cavity cancer patients. The specific aims of the proposed study are to leverage the available diagnostic tumor blocks, demographic and clinical information and survival outcomes of oral cavity cancer patients from five head and neck cancer studies (Fred Hutchinson Cancer Research Center/Univ. of Washington; Univ. of Calgary; Univ. of Michigan; Univ. of Utah; and the International Agency of Research on Cancer) to 1) test the hypothesis that the prognostic ability of our 9-gene signature for HPV-negative OSCC patients, that was developed and validated using snap frozen fresh tumor tissue and Affymetrix gene expression arrays, can be transported to formalin-fixed paraffin embedded (FFPE) hospital tumor blocks of HPV-negative, p16-negative oral cavity cancer patients and NanoString nCounter technology, and to build prediction models for overall and oral cavity cancer-specific survival; 2) validate th prediction models using independent cohorts of HPV-negative, p16-negative oral cavity cancer patients; and 3) evaluate whether the ability of the gene signature to predict survival, overall an OSCC-specific, would be influenced by treatment modalities (surgery alone; surgery + radiation; and surgery + radiation + chemotherapy) that collectively were administered to ~90% of the study participants. This study is significant and novel because it has the potential to deliver, fr the first time, a rapid, inexpensive, and reliable multi-marker assay that can be run on hospital diagnostic FFPE samples, routinely prepared by the hospital at the time of surgery, to improve survival prediction of HPV-negative oral cavity cancer patients, and thus lead to improved clinical care of patients with this often lethal disease.

描述（由申请人提供）：口腔和口咽鳞状细胞癌 (OSCC) 是一个巨大的全球健康负担，估计 2012 年有 529,000 例新病例和超过 292,000 例死亡。OSCC 可以进一步细分为具有不同预后的实体。例如，人乳头瘤病毒 (HPV) 阳性口咽癌 (OPC) 患者往往比 HPV 阴性 OPC 患者有更好的生存率。然而，口腔癌（口腔癌占大多数，且大多数为 HPV 阴性）的预后主要基于临床分期，并且尚未确定可用于临床实践的分子标志物。迫切需要开发更好的预后标志物来对这些患者进行个性化临床管理。我们的长期目标是开发简单、可靠且具有成本效益的基因表达特征来指导 OSCC 患者的管理。在我们之前的工作中（Oralchip 研究，5 R01 CA095419，PI：Chu Chen），我们在肿瘤组织中鉴定了一个预后基因表达特征，该特征比肿瘤分期更能预测 HPV 阴性 OSCC 患者的 OSCC 特异性生存，无论治疗类型如何。我们使用来自 MD 安德森癌症中心的一组独立的口腔癌患者验证了这一特征。这是基因表达特征的首次演示，可为口腔癌患者提供 AJCC 分期以外的预后信息。 拟议研究的具体目的是利用来自五项头颈癌研究（弗雷德·哈钦森癌症研究中心/华盛顿大学、卡尔加里大学、密歇根大学、犹他大学和国际癌症研究机构）的可用诊断肿瘤块、人口统计和临床信息以及口腔癌患者的生存结果来1）测试我们的预测能力的假设 使用速冻新鲜肿瘤组织和 Affymetrix 基因表达芯片开发和验证的 HPV 阴性 OSCC 患者的 9 基因特征，可将其转运至 HPV 阴性、p16 阴性口腔癌患者的福尔马林固定石蜡包埋 (FFPE) 医院肿瘤块和 NanoString nCounter 技术，并建立整体和口腔的预测模型 腔癌特异性生存； 2) 使用 HPV 阴性、p16 阴性口腔癌患者的独立队列验证预测模型； 3) 评估基因特征预测生存的能力（总体而言是 OSCC 特异性的）是否会受到治疗方式（单纯手术；手术 + 放疗；以及手术 + 放疗 + 化疗）的影响，这些治疗方式总共对约 90% 的研究参与者进行。 这项研究具有重要意义和新颖性，因为它有可能首次提供一种快速、廉价且可靠的多标志物测定，可以对医院在手术时常规制备的医院诊断 FFPE 样本进行运行，以提高 HPV 阴性口腔癌患者的生存预测，从而改善患有这种致命疾病的患者的临床护理。