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

摘要 口服 美国人 诊断， 早期 像 使用 临床上， 那里 定义 特征， 性能 甲基化 回顾性 甲基化 后生 个性化 与 构建体 患者 鳞状细胞癌（OSCC）呈上升趋势，在20年内增加了三分之二。每年30，000 被诊断为口腔鳞状细胞癌，其中50%的病例为早期I/II期。尽管在早期阶段， 这些患者具有显著的发病率和40%的5年死亡率。治疗 阶段OSCC是高度可变的，范围从仅仅癌症切除，到添加辅助治疗 选择性颈清扫术（END）、放疗（RT）或放化疗（chemoRT）。虽然阶段主要是 评估风险和分配辅助治疗，其预后价值低。目前还没有可靠 组织学或分子标志物，以确定同一癌症阶段患者的个体风险。 需要开发一种可靠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学组成。 使用发现队列和癌症基因组图谱（TCGA）数据， 以确定5年内死亡风险高的患者。在本申请中，我们建议验证这一点 来自多机构的已知5年生存期的早期OSCC患者的生物标志物 福尔马林固定、石蜡包埋（FFPE）组织的队列。我们将联合收割机 （分子）生物标志物与临床病理学（非分子）标志物结合以构建高风险 和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）， 并对早期口腔鳞癌的回顾性队列（队列1，n=400）进行REASON评分验证 已知5年生存结果，仅接受癌症切除术。第二、 L 我们将应用 REASON评分对一个单独的回顾性队列（队列2，n=400）的早期OSCC患者， 进行辅助治疗（即，END、RT、chemoRT）。我们将确定 这些辅助治疗是否使高风险（高REASON评分）患者的生存率优于 癌症切除术我们还将确定这些辅助治疗是否可以在低风险的情况下省去。 (low REASON评分）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 EWAS with MethylCap-Seq（MC-Seq），一种稳健的临床实验室改进修正案（CLIA） 平台最后，在探索性的目标中，我们将前瞻性地招募早期OSCC患者， 非侵入性刷拭子和癌组织。我们将确定甲基化的一致性 使用MC-Seq在这些患者中配对的刷拭子和癌组织之间进行比较，并确定 在该前瞻性队列（队列3，n=200）中的REASON评分的性能。本研究 迄今为止最大的队列（n=1000）早期OSCC患者，预计将产生 稳健的死亡风险评分。

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.