The genomic landscape and evolution of cutaneous squamous cell carcinoma

项目总结/摘要 皮肤鳞状细胞癌是一种皮肤癌，起源于角质形成细胞， 据估计，美国每年有8000人。与发病率相似的其他癌症相比， 收费，和/或经济负担，我们对基因组景观和遗传进化的理解， 皮肤鳞状细胞癌是有限的。该补助金的首要目标是确定 皮肤鳞状细胞癌中的突变，以描述皮肤鳞状细胞癌的遗传演变， 细胞癌的前体病变，并建立最早的遗传改变发生在前 肿瘤性角质形成细胞。为了实现这些目标，在aim 1中，我们将识别外显子组和基因组中的驱动突变。 测序数据涵盖皮肤鳞状细胞癌。这些数据将从公开的 现有的来源以及来自我们自己机构的新测序数据，共同组成了最大的 皮肤鳞状细胞癌测序数据的分析。在aim 2中，我们将对皮肤 鳞状细胞癌和它们所产生的残余前体病变。大多数皮肤 鳞状细胞癌被发现邻近称为光化性角化病的良性前驱病变， 在这里，我们将分析患者匹配的病变，以揭示驱动良性病变转变的突变， 到恶性状态。在aim 3中，我们将阐明个体中发生的最早的体细胞改变。 正常皮肤的角质形成细胞。正常皮肤的深度测序表明，角质形成细胞可以形成 相关细胞的斑块，有时含有已知会导致皮肤鳞状细胞癌的突变， 但没有研究真正在单细胞分辨率下对角质形成细胞进行基因分型，这在我们对角质形成细胞的认识上留下了空白。 发生在肿瘤形成前角质形成细胞中的初期事件。我们开发了创新的工作流程， 以高特异性和敏感性调用单个皮肤细胞中的突变，使我们能够首次 时间，人类皮肤的基因组改变在单细胞分辨率。 类似的基因组研究已经被证明是推进我们对其他癌症的理解的基础， 揭示干预的治疗点，测量疾病进展的生物标志物， 估计疾病的可能性，并指导最佳预防策略。在这里，我们将解决这些差距， 皮肤鳞状细胞癌知识。总之，完成这些研究将实现 皮肤病学领域的长期目标，这将为新的治疗策略铺平道路 新的预防策略，以减轻皮肤鳞状细胞癌造成的公共卫生负担。

Project Summary/Abstract Cutaneous squamous cell carcinoma is a form of skin cancer, originating from keratinocytes, that kills an estimated 8000 people per year in the United States. Compared to other cancers with similar incidences, death tolls, and/or economic burdens, our understanding of the genomic landscape and genetic evolution of cutaneous squamous cell carcinoma is limited. The overarching goals of this grant are to define the driver mutations in cutaneous squamous cell carcinomas, to delineate the genetic evolution of cutaneous squamous cell carcinomas from precursor lesions, and to establish the earliest genetic alterations occurring in pre- neoplastic keratinocytes. Towards these goals, in aim1, we will identify driver mutations in exome and genome sequencing data covering cutaneous squamous cell carcinoma. This data will be aggregated from publicly available sources as well as new sequencing data from our own institution, collectively comprising the largest analysis of cutaneous squamous cell carcinoma sequencing data to date. In aim2, we will sequence cutaneous squamous cell carcinomas and the remnant precursor lesions from which they arose. Most cutaneous squamous cell carcinomas are discovered adjacent to benign precursor lesions known as actinic keratoses, and here, we will analyze patient-matched lesions to reveal the mutations driving the transition from the benign to the malignant state. In aim3, we will elucidate the earliest somatic alterations occurring in individual keratinocytes from normal skin. Deep sequencing of normal skin has shown that keratinocytes can form patches of related cells, sometimes harboring mutations known to drive cutaneous squamous cell carcinoma, but no studies have truly genotyped keratinocytes at single-cell resolution, leaving gaps in our knowledge of the incipient events that occur in pre-neoplastic keratinocytes. We have developed an innovative workflow to call mutations in individual skin cells with high specificity and sensitivity, permitting us to catalog, for the first time, the genomic alterations in human skin at single-cell resolution. Similar lines of genomic studies have proven fundamental in advancing our understanding of other cancers by revealing therapeutic points of intervention, biomarkers to measure disease progression, biomarkers to estimate disease likelihood, and guidance on the best prevention tactics. Here, we will address these gaps in knowledge for cutaneous squamous cell carcinoma. Taken together, completion of these studies will realize longstanding goals within the field of dermatology, which will pave the way for new treatment strategies and new preventions strategies to alleviate the public health burden posed by cutaneous squamous cell carcinoma.