Molecular basis of melanocytic nevi

黑色素细胞性痣(葡萄胎)是一种非常常见且常活检的良性黑素细胞肿瘤。 是黑色素瘤的模仿物、危险因素和潜在的先兆，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%。如果及早诊断出来， 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，在多达10- 在25%的病例中，病理学家不同意诊断。因此，需要新的标记物来定义两者 黑素细胞肿瘤包括良性和恶性黑素细胞肿瘤，可用于诊断和治疗。而当 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，特别是常见的 获得性和发育不良痣是临床上最常见的色素性皮损，也是有限的。 总体假设是黑色素细胞痣表现出不同于 黑色素瘤。利用这些数据最终将导致开发急需的新的客观诊断 治疗靶点的确定和策略。 第一个目标是确定散发性黑色素细胞痣的基因组图谱，特别是常见的。 获得性和发育不良的痣。假设是nevi在有限数量的关键基因中显示出反复的突变 表明存在分子上不同的雀斑亚型的基因。此外，假设是 基因组图谱与组织学特征相关，组织学特征是目前诊断黑素细胞肿瘤的基础。 我们将进行整个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 异常和突变特征，并将这些与详细的临床和组织学特征相关联。 第二个目标是调查生殖系突变如何影响数量和基因组格局。 内维。具体地说，我们将检查一组患有心脏-面部-皮肤综合征和Costello的患者。 由RAS途径不同基因的胚系突变引起的综合征，这些基因是至关重要的 治疗黑色素瘤。该假说认为某些生殖系RAS途径突变易患 发生痣，但还需要其他的共突变才能发生痣。我们将确定 色素痣是黑色素瘤的最强风险标记物，也是色素痣的皮肤镜检查模式，与 生殖系背景。我们将为整个外显子组和基因组测序收集Rasathnevi，以确定 新生的遗传事件，包括胚系突变在驱动新生中的作用和 潜在的体细胞共突变的存在有助于新生。 通过研究在生殖系RAS途径突变的背景下出现的散发性痣和痣，我们将确定 痣的驱动因素和基因组图景-良性的对应物、模拟物和潜在的前体 黑色素瘤。最终，这些研究将导致确定急需的新的客观诊断 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。

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.