The germline variation in immune and epigenetic pathways and melanoma prognosis

描述(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特征提供了一些信息，但它们以更个性化的方式预测结果的能力是有限的。最近的研究已经提出了一些与黑色素瘤进展相关的分子预测因子，但这些太笼统，不能满足单个患者的预后预测。在我们的研究中，我们假设与免疫反应或表观遗传调节相关的分子通路中的种系遗传因素可能为生物标记物提供个性化的预后能力。我们已经生成了支持这一假设的初步实验数据，我们最终计划将其包括在我们的扩展R01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样本进行全面的遗传图谱分析。由于飓风桑迪的破坏性影响，这些重要的初步实验在计划中的分析之前丢失或以其他方式停止。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常见或罕见的变异及其与黑色素瘤临床结果的关系提供试点证据。在拟议的设计中，我们计划使用COX模型对来自免疫调节和表观遗传途径(包括microRNA位点)的154个基因的&gt；400个常见变异进行基因分型和生存分析，采用两阶段设计，使用1)642名黑色素瘤患者，然后对另外626名患者进行验证分析，这两个队列都是在NYUMC前瞻性地确定的，具有广泛的临床信息(特异性Aim1)。在特定目标2中，我们将通过靶向测序和对两个临床结果极端的德系犹太血统(AJ)患者亚群的相同154个基因(特定目标1)的关联分析，发现与生存相关的罕见突变/变异，以补充常见的变异分析：50名早期复发的AJ患者与50名晚期复发的AJ患者，随后对另外262名AJ黑色素瘤患者进行验证。AJ血统的选择将通过减少遗传异质性并通过识别与生存相关的创始人等位基因来增强分析能力，从而显著改进设计，这些等位基因在AJ患者中共享。这项研究中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，从而加强我们计划的大型R01提案，以全面分析与黑色素瘤预后相关的遗传变化(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生物标记物提供初步证据，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.