The germline variation in immune and epigenetic pathways and melanoma prognosis

描述（由申请人提供）：与黑色素瘤相关的稳定的高死亡率部分是由于预测预后的局限性，特别是对于早期疾病的患者。虽然目前可用的临床病理学特征提供了一些信息，但其以更个性化的方式预测结果的能力有限。最近的研究提出了一些与黑色素瘤进展相关的分子预测因子，但这些预测因子过于笼统，无法满足个体患者的预后预测。在我们的研究中，我们假设与免疫应答或表观遗传调控相关的分子途径中的生殖系遗传因素可能提供具有个性化预后能力的生物标志物。我们已经生成了初步的实验数据来支持这一假设，我们最终计划将其纳入我们的扩展R 01应用程序中，旨在对纽约大学医学中心（NYUMC）建立的患者队列的生殖系和肿瘤标本进行全面的遗传分析。由于飓风桑迪的破坏性影响，这些重要的初步实验在计划的分析之前丢失或停止。当前提案的目标是恢复这些数据，从而为免疫相关和表观遗传途径中的常见或罕见变异及其与黑色素瘤临床结局的相关性提供初步证据。在所提出的设计中，我们计划使用来自免疫调节和表观遗传途径的154个基因（包括微小RNA位点）中>400个常见变体的考克斯模型进行基因分型和存活分析，采用两阶段设计，采用1）642名黑素瘤患者，然后在2）626名患者的额外子集中进行验证分析，两个队列均在NYUMC前瞻性确定，并提供了广泛的临床信息（特定目标1）。在特定目标2中，我们将通过靶向测序发现与生存相关的罕见突变/变异，并对相同的154个基因进行关联分析，（具体目标1）在极端临床结局的德系犹太血统（AJ）的两个患者亚组中：50例早期复发与50例晚期复发AJ患者，随后对另外262例AJ黑色素瘤患者进行验证。AJ祖先的选择将通过减少遗传异质性和通过鉴定AJ患者中共有的与生存相关的创始等位基因来增强分析能力来显著改善设计。这项研究的发现将有助于恢复我们因超级风暴桑迪而丢失或延迟的初步数据，从而增强我们计划的大型R 01提案，以全面分析与黑色素瘤结局相关的遗传改变（生殖系和体细胞）。最重要的是，这些数据将为黑色素瘤预后的潜在新型生物标志物提供试点证据，具有更个性化的临床和生物学潜力。

DESCRIPTION (provided by applicant): The steadily high mortality associated with melanoma is in part be due to the limitations of predicting prognosis, especially for patients with early-stge disease. While currently available clinicopathological characteristics provide some information, their ability to predict outcome in a more personalized fashion is limited. Recent studies have proposed a number of molecular predictors in pathways related to melanoma progression, but these are too general to cater the prognostic prediction to individual patients. In our study we hypothesize that germline genetic factors in the molecular pathways related to immune response or epigenetic regulation may provide biomarkers with personalized prognostic ability. We have generated preliminary experimental data in support of this hypothesis, which we eventually planned to include in our expanded R01 application, aimed at the comprehensive genetic profiling of germline and tumor specimens of patient cohorts established at the New York University Medical Center (NYUMC). With the devastating impact of Hurricane Sandy, these important preliminary experiments were lost or otherwise halted, just before the planned analysis. The goal of the current proposal is to recover this data and hence to provide pilot evidence for the common or rare variants in immune-related and epigenetic pathways and their association with clinical outcomes in melanoma. In the proposed design we plan to perform a genotyping and survival analysis using a Cox model of >400 common variants in 154 genes from immunomodulatory and epigenetic pathways including microRNA sites, in a two stage design employing 1) 642 melanoma patients, followed by a validation analysis in 2) an additional subset of 626 patients, both cohorts prospectively ascertained at NYUMC with extensive clinical information available (Specific Aim1). In Specific Aim 2, we will complement the common variant analysis with the discovery of rare mutations/variants associated with survival by targeted sequencing and an association analysis of the same 154 genes (Specific Aim 1) in two patient subsets of Ashkenazi Jewish ancestry (AJ) of extreme clinical outcomes: 50 early recurrence versus 50 late recurrence AJ patients, followed by validation on an additional 262 AJ melanoma patients. The selection of AJ ancestry will significantly improve the design by reducing the genetic heterogeneity and enhancing the analytical power by identification of founder alleles associated with survival, that are shared among AJ patients. The findings in this study will help in the recovery of our preliminary data lost or delayed by Superstorm Sandy, hence enhancing our planned large R01 proposal for comprehensive analysis of genetic alterations (germline and somatic) associated with melanoma outcomes. Most importantly, the data will provide pilot evidence of potentially novel biomarkers of melanoma prognosis with a more personalized clinical and biological potential.