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: 10188449
• 负责人: MARIANNE BERWICK
• 金额: $ 32.81万
• 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/10188449
• 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; Prognosis; Proteins; Recurrence; Reproducibility; Sentinel Lymph Node; 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 biomarkers; clinical care; clinically actionable; cohort; follow-up; genomic epidemiology; inhibitor/antagonist; ipilimumab; melanoma; melanoma biomarkers; molecular marker; molecular subtypes; mortality; multidisciplinary; mutation screening; next generation sequencing; 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

Abstract 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.

摘要 在这项研究中，我们将确定体细胞肿瘤突变，CNV和黑色素瘤免疫谱与黑色素瘤的关系。 生存率，以确定AJCC TNM IIA-IIIB期中预后不良的患者，并最终 区分哪些患者可以从辅助治疗中获益并挽救生命。我们的假设是 黑色素瘤将具有允许黑色素瘤预后分层的分子和临床特征 这些患者中的肿瘤。目前在这些阶段诊断的个体的存活率范围从 22 - 82%。目前还不清楚哪些患者会进展，哪些不会基于阶段。的 这个项目的最终目的是提供信息，以翻译到诊所，以个性化的护理。 目前，在黑色素瘤领域缺乏研究流行病学/基因组因素， 黑色素瘤存活率，以便鉴定、确认和开发此类生物标志物。我们聚集了九个 1,000名黑色素瘤患者及其肿瘤的队列，其中一半人死于黑色素瘤， 5年（中位生存期为2.4年），一半患者至少生存了5年（中位随访期为8.5 年）。患者将根据分期进行频率匹配。数据将被随机分为660个训练集 肿瘤和340个肿瘤的验证集，按不良和良好预后平均划分。所有病人均已 使用标准护理手术治疗;他们有足够的肿瘤组织，生殖系DNA和临床， 记录病理学和人口统计学信息。 项目1将使用临床可行突变和CNV的靶向下一代测序， 发展患者亚组。其次，我们将评估黑色素瘤免疫概况，CD 3/CD 8/FOXP 3 切片免疫荧光染色和PD 1-PDL 1轴显色染色，以比较强 与存活率相关的病理变量，肿瘤浸润性淋巴细胞（TIL）。我们还将评估比率 CD 8：FOXP 3和CD 8：PD-L1作为预后指标。黑色素瘤免疫特征可能更定量， 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的临床医生，生物统计学家，实验室科学家和流行病学家 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来说，它将有助于确定哪些个体可能预后不良 并有可能发现这些新的辅助治疗和更密切的监测。