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Molecular basis of melanocytic nevi

黑素细胞痣的分子基础

基本信息

批准号：
10683365
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
项目类别：
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/10683365
关键词：
Automobile Driving BRAF gene Benign 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 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 Prevention Publishing RAS genes Recurrence Research Risk Risk Factors Risk Marker Role Skin Skin Cancer Survival Rate Syndrome Therapeutic 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 tumor whole genome

项目摘要

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，并在多达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，我们将研究一组患有面部皮肤综合征和Costello的个体，由Ras途径的各种基因中的生殖系突变引起的综合征，这些基因是关键的用于黑色素瘤生成。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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The "spade sign" as a pathognomonic histopathologic feature of acne keloidalis: Analysis of 33 cases of cicatricial alopecia.

DOI：
10.1016/j.jaad.2021.06.003
发表时间：
2022-06
期刊：
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
影响因子：
13.8
作者：
Fernanda Ortega-Springall, Maria;Kiuru, Maija;Fung, Maxwell A.
通讯作者：
Fung, Maxwell A.

SCALP syndrome with a germline heterozygous DOCK6 mutation and somatic mosaic NRAS Q61R mutation.

具有种系杂合 DOCK6 突变和体细胞嵌合 NRAS Q61R 突变的头皮综合征。

DOI：
10.1111/pde.15184
发表时间：
2023
期刊：
Pediatric dermatology
影响因子：
1.5
作者：
Meyer,SummerN;Simmons,ElaneeM;McPherson,JohnD;Awasthi,Smita;Kiuru,Maija
通讯作者：
Kiuru,Maija

Psychosocial and psychiatric comorbidities and health-related quality of life in alopecia areata: A systematic review.

心理社会和精神病合并症以及与健康相关的生活质量的脱发：系统评价。

DOI：
10.1016/j.jaad.2020.06.047
发表时间：
2021-07
期刊：
Journal of the American Academy of Dermatology
影响因子：
13.8
作者：
Toussi A;Barton VR;Le ST;Agbai ON;Kiuru M
通讯作者：
Kiuru M

Localized calcium oxalate crystals in primary cutaneous aspergillosis.

原发性皮肤曲霉病中的局部草酸钙晶体。

DOI：
10.1111/cup.14533
发表时间：
2024
期刊：
Journal of cutaneous pathology
影响因子：
1.7
作者：
Meyer,SummerN;Le,Stephanie;Caro-Chang,LeahAntoinette;Awasthi,Smita;Fung,MaxwellA;Kiuru,Maija
通讯作者：
Kiuru,Maija

The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukaemia: A systematic review.

1 型神经纤维瘤病患者的幼年黄色肉芽肿与白血病发展之间的关联：系统评价。