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 定义的 特征， 表现 甲基化 回顾性的 甲基化 表观遗传 个性化 和 构造 患者 鳞状细胞癌 (OSCC) 呈上升趋势，20 年来增加了三分之二。每年 30,000 被诊断患有 OSCC，其中 50% 为早期 I/II 期。尽管处于早期阶段 这些患者的发病率很高，5 年死亡率高达 40%。治疗 OSCC 阶段变化很大，从仅癌症切除到添加辅助治疗 选择性颈清扫术 (END)、放疗 (RT) 或化放疗 (chemoRT)。虽然舞台主要是 评估风险并指定辅助治疗，其预后价值较低。目前还没有可靠的 组织学或分子标记，以确定同一癌症阶段患者的个体风险。 需要开发一种稳健的预后生物标志物来指导治疗和提高生存率。我们最近 早期 OSCC 患者的死亡风险评分，由甲基化和临床病理组成 使用发现队列和癌症基因组图谱 (TCGA) 数据，该数据具有很强的预测性 识别5年内死亡高风险的患者。在此应用程序中，我们建议验证这一点 多机构已知 5 年生存期的早期 OSCC 患者的生物标志物 一组福尔马林固定、石蜡包埋 (FFPE) 的组织。我们将结合我们经过验证的 （分子）生物标志物与临床病理（非分子）标志物构建高风险 以及口腔癌临床病理评分 (REASON) 评分。我们假设这 评分将准确预测 5 年癌症特异性死亡率的风险。研究将继续进行 三个目标。首先，我们将使用 EPIC 阵列进行表观基因组广泛关联研究 (EWAS)，以 并通过早期 OSCC 的回顾性队列（队列 1，n=400）验证 REASON 评分 已知 5 年生存结果，仅接受癌症切除术。第二， 我 我们将申请 对早期 OSCC 患者的单独回顾性队列（队列 2，n=400）的 REASON 评分 除癌症切除术外，还接受了辅助治疗（即 END、RT、chemoRT）。我们将确定 这些辅助治疗是否能为高风险（高 REASON 评分）患者带来生存优势 单纯癌症切除术。我们还将确定低风险情况下是否可以免除这些辅助治疗 （原因评分低）患者。 在 可证明的 收集 签名 预后的 组装 临床上 我们还将对发现的甲基化特征进行技术验证 带有 MmethylCap-Seq (MC-Seq) 的 EWAS，这是一项强大的临床实验室改进修正案 (CLIA) 平台。最后，为了探索性目标，我们将前瞻性地招募早期 OSCC 患者并 无创刷拭子和癌组织。我们将确定甲基化的一致性 使用 MC-Seq 在这些患者的配对刷拭子和癌症组织之间进行分析，并确定 该前瞻性队列（队列 3，n=200）中 REASON 评分的表现。这项研究 迄今为止最大的早期 OSCC 患者队列 (n=1000)，预计将产生 稳健的死亡风险评分。