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来自角质形成细胞的皮肤癌的一种形式，可杀死美国估计每年有8000人。与其他发生类似发生率的癌症相比通行费和/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受到限制。这笔赠款的总体目标是定义驾驶员皮肤鳞状细胞癌中的突变，描绘皮肤鳞状的遗传进化从前体病变中的细胞癌，并确定在前的最早的遗传改变肿瘤角质形成细胞。朝着这些目标，在AIM1中，我们将确定外显子和基因组中的驾驶员突变测序数据涵盖皮肤鳞状细胞癌。这些数据将从公开汇总可用来源以及我们自己机构的新测序数据，共同包括最大的迄今为止，皮肤鳞状细胞癌测序数据的分析。在AIM2中，我们将对皮肤序列序列鳞状细胞癌及其出现的残留前体病变。最皮肤鳞状细胞癌被发现与良性前体病变相邻，称为阳光性角膜造成，在这里，我们将分析患者匹配的病变，以揭示从良性过渡的突变到恶性国家。在AIM3中，我们将阐明个人最早发生的躯体变化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，有时含有已知驱动皮肤鳞状细胞癌的突变，但是，没有研究在单细胞分辨率下真正地基因分型角质形成细胞，在我们的知识中留下了差距发生前塑性角质形成细胞中发生的初期事件。我们已经开发了一个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，使我们能够分类。时间，在单细胞分辨率下人类皮肤的基因组改变。类似的基因组研究线已经证明了基本的基础，以促进我们对其他癌症的理解揭示干预的治疗点，测量疾病进展的生物标志物，生物标志物估计疾病的可能性，以及有关最佳预防策略的指导。在这里，我们将解决这些差距皮肤鳞状细胞癌的知识。综上所述，这些研究的完成将意识到皮肤病学领域内的长期目标，这将为新的治疗策略铺平道路减轻皮肤鳞状细胞癌带来的公共卫生负担的新预防策略。