The REASON Score: An Epigenetic And Clinicopathologic Score to Predict Risk of Poor Survival in Early Stage Oral Squamous Cell Carcinoma Patients

REASON 评分：预测早期口腔鳞状细胞癌患者生存不良风险的表观遗传学和临床病理学评分

• 批准号: 10682577
• 负责人: Chi T. Viet
• 金额: $ 74.84万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682577
• 关键词: Adjuvant; Adjuvant Therapy; American; Biological Markers; Biopsy; Clinical; Clinical Laboratory Improvement Amendments; Clinical Research; Clinical Treatment; Data; Diagnosis; Early treatment; Enrollment; Epigenetic Process; Excision; Fingerprint; Formalin; Genes; Goals; Histologic; Individual; Institution; Legal patent; Malignant Neoplasms; Methylation; Modality; Molecular; Morbidity - disease rate; Neck Dissection; Needs Assessment; Oral; Oral Stage; Paraffin Embedding; Pathway Analysis; Patients; Performance; Prognostic Marker; Prospective cohort; Radiation therapy; Retrospective cohort; Risk; Risk Assessment; Squamous cell carcinoma; Stage at Diagnosis; Swab; Techniques; Testing; The Cancer Genome Atlas; Time; Tissue Embedding; Tissues; Tumor stage; Validation; biomarker validation; cancer biomarkers; carcinogenesis; chemoradiation; chemotherapy; clinical decision-making; cohort; epigenome-wide association studies; high risk; improved; malignant mouth neoplasm; molecular marker; mortality; mortality risk; mouth squamous cell carcinoma; overtreatment; prognostic; prognostic performance; prognostic signature; prognostic value; prospective; risk prediction; survival outcome; validation studies

ABSTRACT Oral Americans diagnosis, early like used clinical, There defined features, performance methylation retrospective methylation Epigenetic personalized with construct patients squamous cell carcinoma (OSCC) is on the rise, increasing by two-thirds in 20 years. Each year 30,000 are diagnosed with OSCC, and 50% of these cases are early stage I/II. Despite the early stage at these patients suffer from significant morbidity, and a 5-year mortality rate of 40%. Treatment for stage OSCC is highly variable, ranging from just cancer resection, to the addition of adjuvant treatments elective neck dissection (END), radiotherapy (RT), or chemoradiation (chemoRT). While stage is primarily to assess risk and assign adjuvant treatment, its prognostic value is low. There is currently no reliable histologic or molecular marker to determine individual risk in patients within the same cancer stage. is a need to develop a r obust prognostic biomarker to guide treatment and improve survival. We recently a mortality risk score for early stage OSCC patients, composed of methylation and clinicopathologic using a discovery cohort and The Cancer Genome Atlas (TCGA) data, which has strong predictive to identify patients at high risk of death in 5 years. In this application, we propose to validate this biomarker in early stage OSCC patients with known 5-year survival from a multi-institutional cohort of formalin-fixed, paraffin embedded (FFPE) tissues. We will combine our validated (molecular) biomarker with clinicopathologic (non-molecular) markers to construct the high-Risk And clinicopathologic Score for Oral caNcer ( REASON ) score. We hypothesize that this score wil accurately predict the risk of 5-year cancer-specific mortality . The study will proceed three aims. Firstly, we will perform an epigenome wide association study ( EWAS) using the EPIC array, to and validate the REASON score with a retrospective cohort (cohort 1, n=400) of early stage OSCC with known 5-year survival outcome, who underwent cancer resection only. Secondly, l we will apply the REASON score to a separate retrospective cohort (cohort 2, n=400) of early stage OSCC patients who underwent adjuvant treatments (i.e., END, RT, chemoRT) in addition to cancer resection. We will determine whether these adjuvant treatments confer a survival advantage in high risk (high REASON score) patients over cancer resection alone. We will also determine whether these adjuvant treatments could be spared in low risk (low REASON score) patients. in certifiable collect signatures prognostic assembles clinically We will also perform technical validation of the methylation features discovered the EWAS with MethylCap-Seq (MC-Seq), a robust, Clinical Laboratory Improvement Amendments (CLIA) platform. Lastly, in an exploratory aim, we will prospectively enroll early stage OSCC patients and noninvasive brush swabs and cancer tissues. We will determine the concordance of methylation between paired brush swabs and cancer tissues in these patients using MC-Seq, and determine the performance of the REASON score in this prospective cohort (cohort 3, n=200). This study the largest cohort (n=1000) early stage OSCC patients to date, and is expected to produce a robust mortality risk score.

抽象的 口服 美国人 诊断， 早期的 喜欢 用过的 临床， 那里 定义 特征， 表现 甲基化 回顾 甲基化 表观遗传学 个性化 和 构造 患者 鳞状细胞癌（OSCC）正在上升，在20年内增加了三分之二。每年30,000 被诊断为OSCC，其中50％是早期I/II。尽管早期 这些患者患有明显的发病率，5年死亡率为40％。治疗 OSCC阶段的变化很大，范围从癌症切除到辅助治疗 选修颈解（末端），放疗（RT）或化学放疗（Chemort）。而阶段主要是 为了评估风险并分配辅助治疗，其预后价值很低。目前没有可靠的 组织学或分子标记以确定同一癌症阶段患者的个体风险。 是需要开发预后的生物标志物来指导治疗并提高生存率。我们最近 由甲基化和临床病理学组成的早期OSCC患者的死亡率风险评分 使用发现队列和癌症基因组图集（TCGA）数据，该数据具有很强的预测性 识别5年内处于高死亡风险的患者。在此应用程序中，我们建议对此进行验证 早期阶段OSCC的生物标志物，具有多机构的5年生存率 福尔马林固定的石蜡嵌入（FFPE）组织的队列。我们将结合经过验证的 （分子）生物标志物具有临床病理学（非分子）标记物来构建高风险 口腔癌（理性）评分的临床病理评分。我们假设这是 得分WIL准确地预测了5年癌症特异性死亡率的风险。该研究将继续 三个目标。首先，我们将使用史诗阵列进行一项表观基因组广泛的关联研究（EWAS） 并通过回顾性队列（队列1，n = 400）的早期阶段OSCC验证推理得分 仅接受癌症切除的已知5年生存结果。第二， l 我们将申请 理由得分为单独的回顾性队列（队列2，n = 400）的早期OSCC患者 除了癌症切除外，还接受了辅助治疗（即End，RT，Chemort）。我们将确定 这些辅助治疗是否赋予高风险（高理性评分）患者的生存优势 仅癌症切除。我们还将确定这些辅助治疗是否可以在低风险中幸免 （理性得分低）患者。 在 可认证 收集 签名 预后 组装 临床 我们还将对发现的甲基化特征进行技术验证 带有甲基尺寸序言（MC-SEQ）的EWA，一种健壮的临床实验室改进（CLIA） 平台。最后，在探索目的中，我们将前瞻性地注册OSCC患者和 无创的刷拭子和癌组织。我们将确定甲基化的一致性 在这些患者中使用MC-Seq的配对刷拭子和癌症组织之间，并确定 在此前瞻性队列中，原因得分的表现（队列3，n = 200）。这项研究 迄今为止，最大的队列（n = 1000）早期OSCC患者，预计将产生 强大的死亡风险评分。