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.

抽象的 在这项研究中，我们将确定与与之相关的体细胞肿瘤突变，CNV和黑色素瘤免疫特征 生存是为了确定AJCC TNM阶段IIA-IIIB的预后不良的患者，最终 区分哪些患者可以从适应疗法中获利并挽救生命。我们的假设是主要 黑色素瘤将具有分子和临床特征，将允许黑色素瘤的预后分层 这些患者中的肿瘤。当前在这些阶段诊断的个人的生存率从 22 - 82％。几乎没有了解哪些患者会进展，哪些不会基于阶段。这 该项目的最终意图是提供信息，以转化为诊所以个性化护理。 目前，在黑色素瘤领域的研究死亡，研究流行病学/基因组因素和 黑色素瘤的生存是为了识别，确认和发展此类生物标志物。我们把九个 1,000名患者及其肿瘤的黑色素瘤患者的同伴，一半死于黑色素瘤 五年（中位生存期，2。4年）和一半，他们至少居住了五年（中位随访8.5 年）。患者将与阶段相匹配。数据将随机分为660的培训集 肿瘤和340个肿瘤的验证集，同样由较差和良好的预后分开。所有患者曾经 使用护理标准手术治疗；它们具有足够的肿瘤组织，种系DNA和临床， 记录了病理和人口统计信息。 项目1将使用针对性的临床可行突变和CNV的下一代测序，以便为了 发展患者的亚组。其次，我们将评估黑色素瘤免疫轮廓，CD3/CD8/FOXP3 用免疫荧光和PD1-PDL1轴成色色染色染色的载玻片，以比较强 与存活，肿瘤浸润淋巴细胞（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。黑色素瘤免疫特征可能更定量，并且 比TIL评分可再现，我们将在这项大​​型研究中确定这一点。 最后，我们的临床医生，生物统计学家，实验室科学家和流行病学家的强大多学科团队 将有助于制定新的策略和新信息，以了解与 黑色素瘤的预后。具体来说，它将有助于确定哪些人可能的预后不佳 并有可能确定这些用于新的调整疗法和更仔细的监视。