Molecular basis of melanocytic nevi

黑素细胞痣的分子基础

• 批准号: 10448259
• 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/10448259
• 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; diagnostic strategy; exome sequencing; genome sequencing; genomic signature; improved; melanoma; melanomagenesis; 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.

黑素细胞痣（痣）是极其常见且经常进行活检的良性黑素细胞肿瘤， 是黑色素瘤的模仿者、危险因素和潜在前体，黑色素瘤是最致命的常见皮肤形式 癌症。黑素细胞肿瘤约占所有皮肤活检的 50%。如果及早诊断， 黑色素瘤是可以治愈的。然而，目前的诊断是基于组织学检查，最多需要 10- 25%的病例，病理学家不同意诊断。因此，需要新的标记来定义两者 良性和恶性黑素细胞肿瘤，可用于诊断和作为治疗靶点。尽管 对黑色素瘤进行了广泛的测序工作，对痣进行了类似的研究，尤其是常见的痣 获得性痣和发育不良痣是临床实践中最常见的色素病变，其局限性有限。 总体假设是，黑素细胞痣表现出不同于其他细胞痣的独特基因组特征。 黑色素瘤。利用这些数据最终将导致开发急需的新型客观诊断方法 策略和治疗靶点的确定。 第一个目标是定义散发性黑素细胞痣的基因组景观，特别是常见的 获得性痣和发育不良痣。假设痣在有限数量的关键基因中表现出反复突变 表明存在分子上不同的痣亚型的基因。此外，假设是 基因组景观与组织学特征相关，组织学特征是目前诊断黑素细胞肿瘤的基础。 我们将进行全外显子组和基因组测序，以确定主要驱动因素、共同突变、拷贝数 畸变和突变特征，并将这些与详细的临床和组织学特征相关联。 第二个目标是研究种系突变如何影响数量和基因组景观 痣。具体来说，我们将检查一组患有心-面-皮肤综合征和 Costello 的个体 由 Ras 途径的各种基因的种系突变引起的综合征，这些基因同样至关重要 用于黑色素瘤生成。假设是某些种系 Ras 途径突变易导致 痣的发展，但新生需要额外的共同突变。我们将确定数量 痣是黑色素瘤最强的风险标志物，痣的皮肤镜模式是黑色素瘤的潜在相关因素 种系背景。我们将收集 RAS 病痣进行全外显子组和基因组测序来定义 新生的遗传事件，包括种系突变在驱动新生中的作用以及 存在有助于新生的潜在体细胞共突变。 通过研究在种系 Ras 途径突变的情况下出现的散发性痣和痣，我们将定义 痣的驱动因素和基因组景观 - 痣的良性对应物、模仿物和潜在前体 黑色素瘤。最终，这些研究将导致确定急需的新型客观诊断方法 降低与黑素细胞肿瘤相关的发病率和死亡率的标志物和治疗靶点。