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The genomic landscape and evolution of cutaneous squamous cell carcinoma

皮肤鳞状细胞癌的基因组景观和进化

基本信息

批准号：
10709592
负责人：
Alan Hunter Shain
金额：
$ 40.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709592
关键词：
Acceleration Actinic keratosis Address Attention Automobile Driving Benign Biological Markers Caliber Cataloging Catalogs Cells Cellularity Cessation of life Communities Consensus DNA Sequence Alteration Data Dermatology Development Disease Disease Progression Economic Burden Epidemic Etiology Event Evolution Genes Genetic Genomics Genotype Goals Grant Human Immunotherapy Incidence Individual Infiltration Institution Intervention Knowledge Large-Scale Sequencing Lesion Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of liver Measures Mutation Neoplasms Neoplastic Keratinocyte Oncogenes Patients Persons Phase Prevention Prevention strategy Public Health Renal carcinoma Research Resolution Sensitivity and Specificity Skin Skin Cancer Somatic Mutation Source Stromal Cells Sun Exposure Surgeon The Cancer Genome Atlas Therapeutic Time Tumor Subtype United States biomarker development cancer subtypes cancer type deep sequencing driver mutation drug development exome exome sequencing falls fighting gene discovery genetic evolution genome sequencing high risk improved innovation insight keratinocyte malignant state malignant stomach neoplasm melanoma mortality neoplastic novel therapeutic intervention novel therapeutics premalignant response skin squamous cell carcinoma tumor

项目摘要

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.

项目摘要/摘要皮肤鳞状细胞癌是一种皮肤癌，起源于角质形成细胞，可导致据估计，美国每年有8000人。与其他发病率相似的癌症相比，死亡通行费和/或经济负担，我们对基因组图景和遗传进化的理解皮肤鳞状细胞癌是有限的。这笔拨款的首要目标是定义驱动程序皮肤鳞状细胞癌中的突变，以描绘皮肤鳞状细胞癌的遗传进化从前驱病变中分离出细胞癌，并建立发生在前驱病变中的最早的基因改变肿瘤角质形成细胞。为了实现这些目标，在aim1中，我们将确定外显子组和基因组中的驱动因素突变。皮肤鳞状细胞癌的测序数据。此数据将从公开的可用的来源以及来自我们自己机构的新的测序数据，共同构成了最大的迄今为止皮肤鳞状细胞癌测序数据的分析。在AIM2中，我们将对皮肤进行排序鳞状细胞癌及其产生的残留前驱病变。最肤浅的鳞状细胞癌与称为光化性角化病的良性前驱病变相邻，在这里，我们将分析患者匹配的病变，以揭示推动良性转化的突变变成了恶性状态。在目标3中，我们将阐明个体中最早发生的躯体变化。来自正常皮肤的角质形成细胞。对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，有时含有已知的导致皮肤鳞状细胞癌的突变，但没有研究在单细胞分辨率下对角质形成细胞进行真正的基因分型，这在我们对发生在肿瘤前角质形成细胞中的早期事件。我们开发了一种创新的工作流程来具有高特异性和敏感性的单个皮肤细胞的突变，使我们能够第一次对其进行分类时间，人类皮肤在单细胞分辨率下的基因组变化。类似的基因组研究已经被证明是促进我们对其他癌症的理解的基础，通过揭示干预的治疗点，测量疾病进展的生物标记物，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。综上所述，完成这些研究将实现皮肤科领域的长期目标，这将为新的治疗策略和新的预防策略，以减轻皮肤鳞状细胞癌造成的公共健康负担。