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

摘要 口头的 美国人 诊断， 早些时候 喜欢 使用 临床上， 那里 已定义 功能、 性能 甲基化 回顾 甲基化 表观遗传 个性化 使用 建构 病人 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 被诊断为口腔鳞癌，其中50%是早期I/II期。尽管早期的 这些患者的发病率很高，5年死亡率高达40%。治疗 口腔鳞状细胞癌的分期变化很大，从单纯的癌症切除到附加的辅助治疗。 选择性颈淋巴清扫术(完)、放疗(RT)或放化疗(化疗组)。虽然舞台主要是 评估风险和分配辅助治疗，其预后价值很低。目前还没有可靠的 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。 需要开发一种可预测预后的生物标记物来指导治疗和提高生存率。我们最近 由甲基化和临床病理组成的早期口腔鳞癌患者死亡风险评分 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年内死亡风险较高的患者。在本应用程序中，我们建议验证这一点 多机构已知5年生存率的早期口腔鳞状细胞癌患者的生物标志物 福尔马林固定、石蜡包埋(FFPE)组织队列。我们将结合我们经过验证的 (分子)生物标记物与临床病理(非分子)标记物共同构建高危人群 口腔癌临床病理评分(REASON)评分。我们假设这是 SCORE将准确地预测5年癌症特异性死亡的风险。这项研究将继续进行 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 并与早期口腔鳞癌的回顾队列(队列1，n=400)验证原因评分 已知5年生存结果的患者，仅接受了癌症切除。第二， L 我们会申请 对早期口腔鳞癌患者进行单独的回顾性队列(队列2，n=400)的原因评分 除肿瘤切除外，还接受辅助治疗(即END、RT、化疗RT)。我们将决定 这些辅助治疗是否为高危(高原因评分)患者提供了生存优势 单独的癌症切除。我们还将确定这些辅助治疗是否可以在低风险的情况下幸免。 (低原因评分)患者。 在……里面 可认证的 收款 签名 预言家 装配 临床上 我们还将对发现的甲基化特征进行技术验证 使用甲基帽-SEQ(MC-SEQ)的EWAS，一种强大的临床实验室改进修正案(CLIA) 站台。最后，作为一个探索性的目标，我们将前瞻性地招募早期口腔鳞癌患者和 非侵入性刷子拭子和癌组织。我们将确定甲基化的一致性 用MC-Seq对这些患者的毛刷拭子和癌组织进行检测，并确定 在这个预期队列(队列3，n=200)中的原因得分的表现。本研究 迄今为止规模最大的早期口腔鳞癌患者队列(n=1000)，预计将产生 稳健的死亡风险得分。

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.