PQ3 Cutaneous squamous cell carcinoma: Integrating germline and somatic alterations that underlie tumor progression

PQ3 皮肤鳞状细胞癌：肿瘤进展背后的种系和体细胞改变的整合

基本信息

批准号：
10115644
负责人：
MARYAM Mandana ASGARI
金额：
$ 25.58万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2019-04-16 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115644
关键词：
Affect Age Aging American Americas Area Biology Cell physiology Clinical Clinical Data Collaborations Communities DNA Sequence Alteration DNA Sequence Rearrangement Data Development Diagnosis Disease Environmental Exposure Environmental Risk Factor Etiology Event Evolution Exposure to Genes Genetic Genetic Polymorphism Genetic Risk Genome Genomic approach Genomics Germ-Line Mutation Head and neck structure Health Priorities Healthcare Systems Homeostasis Human Papillomavirus Immunosuppression Incidence Joints Knowledge Lead Link Malignant Neoplasms Modeling Mutation Mutation Analysis Neoplasm Metastasis Nonmetastatic Oncogenes Oncogenic Organ Outcome Pathogenesis Persons Pigmentation physiologic function Predisposition Prevalence Prevention strategy Process Publishing Reproducibility Research Research Personnel Resources Risk Risk Assessment Risk Factors Site Skin Carcinogenesis Smoking Smoking History Somatic Mutation Specimen Squamous cell carcinoma Stratification Sun Exposure Technology The Cancer Genome Atlas Therapeutic Intervention Tissues Transcriptional Activation Treatment Cost UV Radiation Exposure Ultraviolet Rays United States Untranslated RNA Validation Variant Work cancer cell cancer genome cancer genomics cancer risk clinical predictors clinical risk cohort cost data portal diagnostic biomarker driver mutation epidemiology study epigenomics exome exome sequencing genetic epidemiology genetic risk factor genome sequencing genome wide association study genomic data improved innovation member molecular targeted therapies mortality new therapeutic target novel novel diagnostics prevent prognostic repository risk prediction risk variant sex skin cancer prevention skin squamous cell carcinoma sun damage therapeutic biomarker tool transcriptome transcriptome sequencing treatment strategy tumor tumor heterogeneity tumor progression whole genome

项目摘要

ABSTRACT Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States, affecting over a million people annually, and with significant mortality due to metastasis. Despite it prevalence and high treatment costs, cSCCs are not included in large-scale cancer genomics efforts aimed at understanding the genetic changes arising in cancer cells, such as The Cancer Genome Atlas (TCGA) project. Thus, genomic alterations in cSCC have not been comprehensively characterized, and novel, molecularly- targeted treatments have not been developed. This proposal, modeled after TCGA which is co-led by Dr. Gad Getz (Co-I of this application), represents the largest effort of its kind to analyze genomic changes that drive cSCC progression. This critical data is needed to identify targets for novel treatment and prevention strategies of cSCC. Our team was the first to publish a genome-wide association study that identified ten novel germline loci associated with increased cSCC risk using the large Genetic Epidemiology Research on Aging (GERA) cohort. The overall scientific objective of this proposal is to identify and integrate novel tumor mutational data with previously characterized information on host genetic risk factors and clinical risk factors to better understand how cancer risk alleles contribute to the development of cSCCs capable of metastasis. We will analyze 290 cSCCs (145 primary cSCCs that progressed to metastasis and 145 non- metastatic primary cSCCs) arising in the well-characterized GERA cohort to provide a comprehensive landscape of genomic alterations in cSCCs. We propose the following specific aims: 1) characterize the genome and transciptome of 290 cSCCs with existing germline data using a tiered approach including whole- exome, whole-genome, and RNA sequencing to identify driver mutations, as well as epigenomic changes;; 2) integrate the somatic mutational analysis with environmental exposure data to understand how environmental exposures impact cSCCs with distinct somatic mutational profiles;; and 3) develop a clinically meaningful risk prediction tool for identifying subjects at risk for metastatic cSCCs that combines germline, somatic, and clinical data. The approach is innovative because it will increase understanding of the joint contribution of the germline and somatic genomes for cSCC risk and it will create a publicly accessible cSCC genomic data portal providing a novel resource for the scientific community. The proposed research is significant because it will integrate germline and somatic genetic data to gain a comprehensive picture of how the genetics of both the person and the tumor interact to affect cSCC evolution and progression. The comprehensive, integrated characterization of key genomic changes in one of the most prevalent and costly cancers will support advances in developing more effective ways to diagnose, treat and prevent cSCCs and potentially squamous cell carcinoma arising in other organs.

抽象的皮肤鳞状细胞癌 (cSCC) 是美国第二大常见癌症，每年影响超过一百万人，尽管其普遍存在，但由于转移而导致的死亡率很高。且治疗成本高，cSCC 并未包含在针对癌症的大规模癌症基因组学研究中了解癌细胞中出现的遗传变化，例如癌症基因组图谱 (TCGA) 项目。因此，cSCC 中的基因组改变尚未得到全面表征，并且新的、分子学上的改变尚未得到全面表征。该提案以 Gad 博士共同领导的 TCGA 为蓝本，目前尚未开发出来。 Getz（本申请的 Co-I）代表了同类中分析驱动基因组变化的最大努力。 cSCC 进展需要这些关键数据来确定新的治疗和预防策略的目标。我们的团队是第一个发表全基因组关联研究的人，该研究鉴定了十种新的种系。使用大型衰老遗传流行病学研究 (GERA) 确定与 cSCC 风险增加相关的位点该提案的总体科学目标是识别和整合新肿瘤。具有先前表征的宿主遗传风险因素和临床风险信息的突变数据更好地了解癌症风险等位基因如何促进 cSCC 发展的因素我们将分析 290 个 cSCC（145 个进展为转移的原发性 cSCC 和 145 个非转移性 cSCC）。转移性原发性 cSCC）出现在特征明确的 GERA 队列中，以提供全面的我们提出以下具体目标：1）表征 cSCC 的基因组改变。使用分层方法（包括整体）对 290 个 cSCC 的基因组和转录组以及现有种系数据进行分析外显子组、全基因组和 RNA 测序，以识别驱动突变以及表观基因组变化；2) 将体细胞突变分析与环境暴露数据相结合，以了解环境如何影响暴露会影响具有不同体细胞突变谱的 cSCC；以及 3) 产生具有临床意义的风险预测工具，用于识别有转移性鳞状细胞癌风险的受试者，结合种系、体细胞和该方法是创新的，因为它将增加对临床数据共同贡献的理解。种系和体细胞基因组用于 cSCC 风险，它将创建一个可公开访问的 cSCC 基因组数据门户拟议的研究为科学界提供了一种新颖的资源，因为它将具有重要意义。整合种系和体细胞遗传数据，以全面了解两者的遗传学如何人与肿瘤相互作用，影响鳞状细胞癌的进化和进展。最常见和最昂贵的癌症之一的关键基因组变化的表征将支持在开发更有效的方法来诊断、治疗和预防鳞状细胞癌和潜在鳞状细胞癌方面取得了进展其他器官中的细胞癌增多。