Molecular basis of melanocytic nevi

黑素细胞痣的分子基础

• 批准号: 10004565
• 负责人: Maija Helena Tuulia Kiuru
• 金额: $ 16.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004565
• 关键词: Automobile Driving; BRAF gene; Benign; Biological Response Modifier Therapy; Biopsy; Biopsy Specimen; Characteristics; Clinical; Costello syndrome; Critical Pathways; Data; Development; Diagnosis; Diagnostic; Dysplasia; Dysplastic Nevus; Early Diagnosis; Event; Genes; Genetic; Genomics; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Histologic; Individual; Knowledge; Lead; Lesion; MAP2K1 gene; Malignant - descriptor; Melanocytic Neoplasm; Melanocytic nevus; Microscope; Mole the mammal; Molecular; Morbidity - disease rate; Mutation; Nevi and Melanomas; Nevus; Oncogenes; Pathologist; Pathway interactions; Pattern; Photography; Pigments; Prevention; Publishing; RAS genes; Recurrence; Research; Risk; Risk Factors; Risk Marker; Role; Skin; Skin Cancer; Survival Rate; Syndrome; base; biomarker identification; cardiofaciocutaneous syndrome; clinical practice; cohort; diagnostic biomarker; exome sequencing; genome sequencing; genomic signature; improved; melanoma; molecular subtypes; mortality; novel; novel marker; prospective; therapeutic target; whole genome

Melanocytic nevi (moles) are exceedingly common and commonly biopsied benign melanocytic neoplasms that are mimics, risk factors, and potential precursors for melanoma, the deadliest of the common forms of skin cancer. Melanocytic neoplasms comprise approximately 50% of all skin biopsies performed. If diagnosed early, melanoma is curable. However, the diagnosis is currently based on histological examination and in up to 10- 25% of cases, pathologists do not agree on the diagnosis. Therefore, novel markers are needed that define both benign and malignant melanocytic neoplasms and could be used for diagnosis and as therapeutic targets. While extensive sequencing efforts have been conducted on melanoma, similar studies on nevi, especially common acquired and dysplastic nevi, the most common pigmented lesions in clinical practice, are limited. The overall hypothesis is that melanocytic nevi show distinct genomic signatures different from melanoma. Utilizing these data will ultimately lead to development of much needed novel objective diagnostic strategies and identification of therapeutic targets. The first aim is to define the genomic landscape of sporadic melanocytic nevi, specifically common acquired and dysplastic nevi. The hypothesis is that nevi show recurrent mutations in a limited number of key genes indicating the existence of molecularly distinct nevus subtypes. Furthermore, the hypothesis is that the genomic landscape correlates with histological features, the current basis for diagnosis of melanocytic tumors. We will perform whole exome and genome sequencing to define main drivers, co-mutations, copy number aberrations, and mutation signatures, and correlate these with detailed clinical and histological features. The second aim is to investigate how germline mutations influence the number and genomic landscape of nevi. Specifically, we will examine a cohort of individuals with Cardio-Facio-Cutaneous syndrome and Costello syndrome caused by germline mutations in various genes of the Ras pathway, the same genes that are critical for melanomagenesis. The hypothesis is that certain germline Ras pathway mutations predispose to the development of nevi but additional co-mutations are required for nevogenesis. We will determine the number of nevi, the strongest risk marker of melanoma, as well as the dermoscopic pattern of nevi, a potential correlate of the germline background. We will collect RASopathy nevi for whole exome and genome sequencing to define genetic events of nevogenesis, including the role of the germline mutation in driving nevogenesis and the presence of potential somatic co-mutations contributing to nevogenesis. By studying sporadic nevi and nevi arising in the setting of germline Ras pathway mutations we will define the drivers and genomic landscape of nevi - the benign counterparts, mimics and potential precursors of melanoma. Ultimately, these studies will lead to identification of much needed novel objective diagnostic markers and therapeutic targets reducing morbidity and mortality related to melanocytic neoplasms.

黑素细胞NEVI（摩尔）非常普遍，并且通常是活检的良性黑色素细胞肿瘤 是模仿，危险因素和黑色素瘤的潜在前体，这是皮肤的最致命形式 癌症。黑素细胞肿瘤约占进行所有皮肤活检的50％。如果早点诊断 黑色素瘤是可以治愈的。但是，该诊断目前基于组织学检查，最多10-- 25％的病例，病理学家不同意诊断。因此，需要定义两个新颖的标记 良性和恶性黑素细胞肿瘤，可用于诊断和治疗靶标。尽管 已经对黑色素瘤进行了广泛的测序工作，对NEVI的类似研究，尤其是常见的 获得和异型症NEVI是临床实践中最常见的色素病变，受到限制。 总体假设是，黑素细胞NEVI显示出不同的基因组特征 黑色素瘤。利用这些数据最终将导致急需的新型目标诊断发展 策略和治疗目标的识别。 第一个目的是定义散发性黑色素细胞NEVI的基因组景观，特别是常见 获得和发育不良的NEVI。假设是Nevi在有限数量的密钥中显示出复发突变 表明存在分子不同的奈夫亚型的基因。此外，假设是 基因组景观与组织学特征相关，这是诊断黑色素肿瘤的当前基础。 我们将执行整个外显子组和基因组测序，以定义主要驱动因素，共突变，副本编号 畸变和突变特征，并将其与详细的临床和组织学特征相关联。 第二个目的是研究种系突变如何影响数量和基因组景观 nevi。具体而言，我们将检查有心脏 - 富西氏综合症和Costello的人群 由Ras途径的各种基因的种系突变引起的综合征，与关键的相同基因 用于黑色素作。假设是某些种系Ras途径突变易于 Nevi的发展，但需要额外的共杀伤。我们将确定 Nevi，是黑色素瘤的最强风险标记，以及Nevi的皮肤镜模式，潜在的相关性 种系背景。我们将收集用于整个外显子组和基因组测序的Rasopathy Nevi以定义 神经发生的遗传事件，包括种系突变在驱动神经发生和 存在潜在的体细胞共突变，导致源源不断。 通过研究在种系RAS途径突变的环境中产生的零星Nevi和Nevi我们将定义 Nevi的驱动因素和基因组景观 - 良性对应物，模仿和潜在的前体 黑色素瘤。最终，这些研究将导致急需的新型客观诊断识别 标志物和治疗靶标可降低与黑素细胞肿瘤有关的发病率和死亡率。