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

项目 1：通过靶向测序和临床病理学评估原发性黑色素瘤分子亚型和结果

• 批准号: 10268362
• 负责人: MARIANNE BERWICK
• 金额: $ 1.2万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268362
• 关键词: Adjuvant; Adjuvant Therapy; Adverse effects; Adverse event; American Joint Committee on Cancer; BRAF gene; Biological Markers; CD3 Antigens; CD8B1 gene; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Colon Carcinoma; Copy Number Polymorphism; DNA; Data; Data Set; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Dose; Epidemiologist; Epidemiology; FOXP3 gene; Frequencies; Genetic; Genomics; Goals; Immune; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Individual; Interferon-alpha; International Union Against Cancer; Laboratory Scientists; MEKs; Molecular; Mutation; Neoplasm Metastasis; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Positive Lymph Node; Proteins; Recurrence; Reproducibility; Sentinel Lymph Node; Sex Differences; Slide; Somatic Mutation; Stage at Diagnosis; Stains; Stratification; Survival Rate; System; TNM; Time; Training; Translating; Tumor Markers; Tumor Tissue; Tumor stage; Validation; actionable mutation; base; clinical care; clinically actionable; cohort; follow-up; genomic epidemiology; inhibitor/antagonist; melanoma; methylome; molecular subtypes; mortality; multidisciplinary; mutation screening; next generation sequencing; outcome forecast; patient stratification; patient subsets; personalized care; prognostic; programmed cell death ligand 1; programmed cell death protein 1; programs; promoter; secondary endpoint; standard of care; statistics; targeted sequencing; tumor

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

在这项研究中，我们将鉴定与以下疾病相关的体细胞肿瘤突变、CNV 和黑色素瘤免疫特征： 生存率，以识别 AJCC TNM IIA-IIIB 期预后不良的患者，并最终 区分哪些患者可以从辅助治疗中受益并挽救生命。我们的假设是主要的 黑色素瘤具有分子和临床特征，可以对黑色素瘤进行预后分层 这些患者中的肿瘤。目前在这些阶段诊断的个体的生存率范围为 22 – 82%。根据分期，人们对哪些患者会进展、哪些不会进展知之甚少。这 该项目的最终目的是向诊所提供信息以实现个性化护理。 目前，黑色素瘤领域缺乏流行病学/基因组因素和 黑色素瘤存活率，以便识别、确认和开发此类生物标志物。我们聚集了九个人 由 1,000 名黑色素瘤患者及其肿瘤组成的队列，其中一半死于黑色素瘤 五年（中位生存期 2.4 年），一半的人至少活了五年（中位随访 8.5 年） 年）。患者将根据阶段进行频率匹配。将数据随机分为660个训练集 肿瘤和 340 个肿瘤的验证集，按预后不良和良好划分。所有患者均已 使用标准护理手术进行治疗；他们有足够的肿瘤组织、种系 DNA 和临床， 记录病理和人口统计信息。 项目 1 将使用临床上可行的突变和 CNV 的靶向下一代测序，以便 开发患者亚组。其次，我们将评估黑色素瘤免疫特征 CD3/CD8/FOXP3 用免疫荧光和 PD1-PDL1 轴显色染色染色的载玻片，以与强 与生存、肿瘤浸润淋巴细胞（TIL）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。黑色素瘤免疫谱可能更加定量和 比 TIL 评分具有可重复性，我们将在这项大​​型研究中确定这一点。 最后，我们强大的多学科团队由临床医生、生物统计学家、实验室科学家和流行病学家组成 将有助于制定新策略和新信息来了解与相关的分子因素 黑色素瘤的预后。具体来说，它将有助于确定哪些人可能预后不良 并有可能识别这些疾病以用于新的辅助治疗和更密切的监测。 项目