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。最近的研究提出了一些与黑色素瘤进展相关的分子预测因子，但这些过于笼统，无法满足个体患者的预后预测。在我们的研究中，我们假设与免疫反应或表观遗传调控相关的分子途径中的种系遗传因子可能提供具有个性化预后能力的生物标志物。我们已经生成了支持这一假设的初步实验数据，我们最终计划将其纳入我们扩展的R01应用程序，旨在对纽约大学医学中心（NYUMC）建立的患者队列的种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要么失去了，要么就在计划的分析开始之前停止了。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的常见或罕见变异及其与黑色素瘤临床结果的关联提供初步证据。在拟议的设计中，我们计划使用来自免疫调节和表观遗传途径（包括microRNA位点）的154个基因中的bbbb400个常见变异的Cox模型进行基因分型和生存分析，在两阶段设计中使用642名黑色素瘤患者，然后在2)额外的626名患者中进行验证分析，这两个队列都是在NYUMC前瞻性确定的，具有广泛的临床信息（Specific Aim1）。在Specific Aim 2中，我们将通过靶向测序发现与生存相关的罕见突变/变异来补充常见变异分析，并对两个具有极端临床结果的德系犹太血统（AJ）患者亚群（50例早期复发与50例晚期复发AJ患者）中相同的154个基因（Specific Aim 1）进行关联分析，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与生存相关的创始等位基因来提高分析能力，从而显著改善设计，这些等位基因在AJ患者中共享。这项研究的发现将有助于恢复我们在超级风暴桑迪中丢失或延迟的初步数据，从而增强我们计划的大型R01提案，对与黑色素瘤结果相关的遗传改变（种系和体细胞）进行综合分析。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.