Project 1: Targeted sequencing and clinicopathology to evaluate primary melanoma molecular subtypes and outcomes

在这项研究中，我们将确定体细胞肿瘤突变、CNV和黑色素瘤免疫图谱与 在AJCC、TNM分期IIA-IIIB和最终确定预后不良的患者的生存期 区分哪些患者可以从辅助治疗中受益并拯救生命。我们的假设是主要的 黑色素瘤将具有分子和临床特征，这将使黑色素瘤的预后分层。 这些患者中的肿瘤。在这些阶段确诊的个体目前的存活率范围为 22%-82%。对于哪些患者会进展，哪些患者不会根据分期进展，人们几乎不了解。这个 这个项目的最终目的是提供信息，以翻译到诊所，实现个性化护理。 目前，在黑色素瘤领域缺乏研究流行病学/基因组因素和 黑色素瘤的存活率，以便识别、确认和开发此类生物标志物。我们已经召集了九个人 1000名黑色素瘤患者及其肿瘤的队列，其中一半死于黑色素瘤 五年(中位生存期，2.4年)和一半至少生活了五年(中位随访8.5年) 年)。患者将在分期上进行频率匹配。数据将被随机分成660个训练集 肿瘤和340个肿瘤的验证集，按预后差和好平均划分。所有的病人都接受了 使用标准护理手术进行治疗；他们有足够的肿瘤组织，生殖系DNA和临床， 记录病理和人口统计信息。 项目1将使用临床上可操作的突变和CNV的有针对性的下一代测序，以便 发展患者亚群。其次，我们将评估黑色素瘤免疫模式CD3/CD8/FOXP3 玻片用免疫荧光染色和PD1-PDL1轴显色染色，以比较强 与生存、肿瘤浸润性淋巴细胞性(TILs)相关的病理变量。我们还将评估比率 CD8：Foxp3和CD8：PD-L1作为预后指标。黑色素瘤免疫图谱可能更加定量和 重复性比TIL评分高，我们将在这项大型研究中确定这一点。 最后，我们由临床医生、生物统计学家、实验室科学家和流行病学家组成的强大的多学科团队 将有助于开发新的策略和新的信息，以了解与 黑色素瘤的预后。具体地说，它将有助于确定哪些人的预后可能较差 并有可能确定这些新的辅助治疗和更密切的监测。 项目

In this study, we will identify somatic tumor mutations, CNVs and a melanoma immune profile in relationship to survival in order to identify patients with poor prognosis among AJCC TNM Stages IIA-IIIB and eventually distinguish which patients may profit from adjuvant therapies and save lives. Our hypothesis is that primary melanomas will have molecular and clinical features that will allow the prognostic stratification of melanoma tumors among these patients. The current survival rate of individuals diagnosed at these stages ranges from 22 – 82%. There is little understanding of which patients will progress and which will not based on stage. The ultimate intent of this project is to provide information to translate to the clinic to personalize care. Currently, there is a dearth of studies in the melanoma field looking at epidemiology/genomic factors and melanoma survival in order to identify, confirm and develop such biomarkers. We have brought together nine cohorts of melanoma patients of 1,000 individuals and their tumors, half who have died from melanoma within five years (median survival, 2.4 years) and half who have lived for at least five years (median follow up 8.5 years). Patients will be frequency matched for stage. Data will be randomly divided into a training set of 660 tumors and a validation set of 340 tumors, equally divided by poor and good prognosis. All patients have been treated using standard-of-care surgery; they have adequate tumor tissue, germline DNA and clinical, pathologic and demographic information recorded. Project 1 will use targeted next generation sequencing of clinically actionable mutations and CNV’s in order to develop subgroups of patients. Secondly, we will evaluate a melanoma immune profile, CD3/CD8/FOXP3 slides stained with immunofluorescence and PD1-PDL1 axis chromogenic staining, to compare to a strong pathologic variable associated with survival, tumor infiltrating lymphoctyes (TILs). We will also evaluate ratios of CD8:FOXP3 and CD8:PD-L1 as prognostic. The melanoma immune profile may be more quantitative and reproducible than TIL score and we will determine this in this large study. Finally, our strong multidisciplinary team of clinicians, biostatisticians, laboratory scientists and epidemiologists will help to develop new strategies and new information to understand molecular factors associated with prognosis in melanoma. Specifically, it will help to identify which individuals are likely to have a poor prognosis and potentially identify these for new adjuvant therapy and closer surveillance. Project