Molecular basis of melanocytic nevi

黑素细胞痣的分子基础

• 批准号: 10214534
• 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/10214534
• 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; 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）是非常常见的，通常活检良性黑素细胞肿瘤， 是黑色素瘤的模拟物、危险因素和潜在的前体，黑色素瘤是最致命的常见皮肤病。 癌黑色素细胞肿瘤约占所有皮肤活检的50%。如果早期诊断， 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，需要新的标记物来定义这两者。 良性和恶性黑素细胞肿瘤，可用于诊断和作为治疗靶点。而 已经对黑色素瘤进行了广泛的测序工作，对痣的类似研究，特别是常见的 获得性和发育不良性痣是临床实践中最常见的色素性病变，但其局限性有限。 总的假设是，黑素细胞痣显示出与黑素细胞痣不同的基因组特征。 黑素瘤利用这些数据将最终导致开发急需的新的客观诊断 策略和治疗靶点的识别。 第一个目的是确定散发性黑素细胞痣的基因组分布，特别是常见的黑素细胞痣。 获得性和发育不良痣。假设痣在有限数量的关键基因中显示复发性突变， 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，这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。 第二个目标是研究生殖系突变如何影响数量和基因组景观 关于Nevi具体来说，我们将检查一组患有心面皮肤综合征和科斯特洛的患者 由Ras途径的各种基因中的生殖系突变引起的综合征，这些基因是关键的 黑色素瘤假设是某些生殖系Ras途径突变易患 痣的发展，但需要额外的共突变痣。我们将确定 痣是黑色素瘤最强的风险标志，以及痣的皮肤镜模式，是黑色素瘤的潜在相关因素。 生殖系背景。我们将收集RAS病痣进行全外显子组和基因组测序， 神经发生的遗传事件，包括生殖系突变在驱动神经发生中的作用， 存在潜在的体细胞共突变，导致神经瘤发生。 通过研究散发性痣和生殖系Ras通路突变引起的痣，我们将定义 痣的驱动因素和基因组景观-良性对应物，模仿物和潜在的前体 黑素瘤最终，这些研究将找到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记物和治疗靶点。