Molecular and immunologic evolution of melanomas from pre-neoplastic lesions

肿瘤前病变黑色素瘤的分子和免疫学进化

• 批准号: 10005924
• 负责人: Boris C. Bastian
• 金额: $ 95.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005924
• 关键词: Algorithms; Automobile Driving; Behavior; Benign; Biological; Biological Markers; Cancer Detection; Cessation of life; Clinical; Complement; Development; Diagnostic; Disease; Early treatment; Equilibrium; Event; Evolution; Goals; Immune response; Immunologics; Individual; Indolent; Investigation; Lesion; Light; Malignant - descriptor; Malignant Neoplasms; Melanocytic Neoplasm; Methods; Molecular; Molecular Analysis; Mutation; Outcome; Patients; Primary Lesion; Prognostic Marker; Risk stratification; Taxonomy; Testing; Translating; Tumor-infiltrating immune cells; Validation; advanced disease; base; cancer genome; cancer prevention; cohort; diagnostic biomarker; follow-up; genetic evolution; high risk; improved; improved outcome; insight; melanoma; multiple omics; neoplastic; neoplastic cell; prognostic; screening; sound; tumor; tumor-immune system interactions

Project Summary/Abstract Tremendous advances in the molecular analysis of melanomas and their immune microenvironment have provided mechanistic insights, which in turn have translated into remarkable improvements to treat and even cure patients with advanced disease. However, many patients still succumb to their disease, in part because treatment starts too late. Identifying patients in need of systemic treatment earlier and removing pre-neoplastic lesions before they evolve into cancer are promising effective ways to reduce melanoma-related deaths. Current screening methods can detect lesions with a broad spectrum of natural behavior-- from those with lethal potential to the completely benign. There is an urgent need to develop precision molecular tests to: (1) Distinguish between benign and malignant lesions (i.e., diagnostic biomarkers); (2) Differentiate biologically indolent versus aggressive tumors in need of additional treatment (i.e., prognostic biomarkers); (3) Identify high-risk individuals who should be screened (i.e., screening biomarkers). My group is performing multi-omics studies on primary lesions to study the earliest molecular and cellular events associated with melanoma initiation and evolution to obtain key insights that are essential to improve risk stratification of early stage cancers, cancer prevention and detection. Characterizing the genetic evolution of main melanoma subtypes as they develop from their respective pre-neoplastic lesions is one major goal of this proposal, as is developing a biomarker-based taxonomy, which will serve as framework for developing significantly advanced diagnostic and prognostic algorithms. Studies of the tumor genome will be complemented by characterization of the composition and functional state of immune cell infiltrates during melanoma evolution to shed light on the interaction between the immune cell infiltrate and tumor cells. The combined analysis of tumor genomes and host response will reveal key mechanisms driving elimination, equilibrium, and ultimate escape and allow us to extract biomarkers, which will undergo validation in patients with known outcomes with the goal to develop clinically sound tests. Specifically, we will formulate candidate algorithms that can (i) better anticipate metastatic dissemination than current methods and (ii) predict whether a pre-neoplastic lesion is likely to progress to melanoma, and validate them using patient cohorts with known follow-up information.

项目总结/摘要 黑色素瘤及其免疫微环境的分子分析取得了巨大进展 提供了机械的见解，这反过来又转化为显着的改善， 治疗甚至治愈晚期疾病患者。然而，许多患者仍然屈服于他们的 疾病，部分原因是治疗开始得太晚。确定需要系统治疗的患者 在癌前病变发展成癌症之前， 来减少黑色素瘤相关的死亡目前的筛查方法可以检测出具有广泛 自然行为的范围--从具有致命潜力的到完全良性的。有一个 迫切需要开发精确的分子测试，以： (1)区分良性和恶性病变（即，诊断生物标志物）; (2)区分生物学惰性与需要额外治疗的侵袭性肿瘤 (i.e.,预后生物标志物）; (3)确定应进行筛查的高风险个体（即，筛选生物标志物）。 我的小组正在对原发性病变进行多组学研究，以研究最早的分子和 与黑色素瘤发生和演变相关的细胞事件，以获得关键的见解， 对改善早期癌症的风险分层、癌症预防和检测至关重要。 描述主要黑色素瘤亚型的遗传进化，因为它们从各自的 肿瘤前病变是该提议的一个主要目标，正如开发基于生物标志物的分类学， 它将作为开发显著先进的诊断和预后的框架， 算法肿瘤基因组的研究将通过组成的表征来补充 和功能状态的免疫细胞浸润在黑色素瘤的演变， 免疫细胞浸润和肿瘤细胞之间的联系肿瘤基因组与宿主的联合分析 反应将揭示驱动消除、平衡和最终逃逸的关键机制， 我们提取生物标志物，将在具有已知结果的患者中进行验证， 来开发临床上可靠的测试。具体来说，我们将制定候选算法，可以（i）更好地 预测转移性传播比目前的方法和（ii）预测是否有肿瘤前 病变可能进展为黑色素瘤，并使用已知随访的患者队列进行验证 信息.