Genetic analysis of ras mutation specificity in skin and lung cancer

皮肤癌和肺癌中ras突变特异性的遗传分析

基本信息

批准号：
9191353
负责人：
ALLAN BALMAIN
金额：
$ 36.26万
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：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191353
关键词：
Alleles Architecture BRAF gene Binding Bioinformatics Biological Assay Biology Butylated Hydroxytoluene Cancer Burden Cancer Model Cancer Prognosis Carcinogens Carcinoma Cells Characteristics Clinical Colon Adenocarcinoma Colonic Neoplasms Common Neoplasm Cutaneous Dangerousness Data Data Set Development Epithelial Cells Exhibits FRAP1 gene Family Family member Frequencies GTP Binding Gene Activation Gene Chips Gene Expression Gene Family Gene Mutation Genes Genetic Growth Factor HRAS gene Head and neck structure Histologic Histology Human In Vitro Individual Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent KRAS2 gene Knock-out Knockout Mice Lead Link Location LoxP-flanked allele Lung Lung Adenocarcinoma Lung Inflammation Lung Neoplasms MEKs Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Molecular Analysis Monitor Mouse Strains Mus Mutant Strains Mice Mutate Mutation Nature Neoplasms Normal tissue morphology Nose Oncogenes Oncogenic Oral cavity Pancreatic Adenocarcinoma Pathway Analysis Pathway interactions Patients Pattern Phenotype Point Mutation Population Predisposition Prevention strategy Preventive Process Protein Isoforms RAS Family Gene RAS genes Ras Signaling Pathway Regenerative response Reporter Resistance Role Route Sampling Shapes Signal Pathway Signal Transduction Skin Skin Cancer Skin Carcinoma Skin Neoplasms Specificity Squamous cell carcinoma Stimulus System Systems Biology Testing The Cancer Genome Atlas Therapeutic Tissues base cancer prevention cancer therapy cancer type cell growth chemical carcinogen comparative conditional mutant design genetic analysis in vivo inhibitor/antagonist insight keratinocyte loss of function lung Carcinoma member mouse model mutant novel outcome forecast pancreatic neoplasm prevent public health relevance response stem-like cell tissue regeneration tool tumor

项目摘要

DESCRIPTION (provided by applicant): Activating mutations in genes of the RAS family are the most common dominant acting oncogenic changes in human cancers. These tumors are particularly difficult to treat, and have a very poor prognosis. Mutations in RAS family members exhibit tissue specificity, but we do not know how tissue damage, inflammation and the resultant remodeling process results in early selection of cells carrying specific mutations in individual RAS isoforms. Mutations in the HRAS gene are mainly found in squamous carcinomas (SCCs) of the lung, skin, and head and neck, which share many histological and molecular characteristics and together constitute a major human cancer burden worldwide. In contrast, KRAS is the most commonly mutated oncogene in adenocarcinomas of the lung, pancreas, and colon. The same tissue specificity is observed in mouse cancer models: carcinogen-induced squamous tumors of the skin have almost 100% Hras mutations, whereas lung adenocarcinomas induced by the same carcinogen have almost 100% Kras mutations. The identification of the factors that underlie this specificity would provide important information tht may lead to tissue-specific or mutation-specific routes to cancer prevention or treatment. We generated novel mouse models in which the specificity for particular Ras isoforms in skin and lung has been reversed or eliminated, resulting in mice that develop Kras mutant skin carcinomas, Hras mutant lung carcinomas, or are completely resistant to chemical carcinogen treatment. This project will exploit these novel mouse models as well as computational network approaches to the identification of functions of Ras genes in normal tissue and carcinomas driven by either Hras or Kras. Mouse gene expression network data will be validated in human samples by integration with human gene expression datasets from squamous carcinomas of the lung and head and neck (generated by TCGA) or in primary cutaneous SCCs, in particular with human SCCs from BRAF-inhibitor treated patients which have an elevated frequency of HRAS (Q61L) gene mutations - exactly the same point mutation that is found in Hras mutant mouse skin tumors. We will use a Systems Biology approach to visualize the architecture of Ras signaling in whole tissues in vivo and in epithelial cells derived from mutant mice, to examine the relationships between inflammation and susceptibility to development of Hras- or Kras-driven malignancies. This comprehensive systems-based approach will reveal conserved features of squamous carcinoma formation that will first help us to understand the genesis of these neoplasms, and begin to formulate strategies for prevention or treatment.

描述（由申请人提供）：RAS家族基因的激活突变是人类癌症中最常见的显性致癌变化。这些肿瘤特别难以治疗，并且预后非常差。 RAS家族成员的突变表现出组织特异性，但我们不知道组织损伤、炎症和由此产生的重塑过程如何导致早期选择携带个体RAS亚型特定突变的细胞。 HRAS基因突变主要见于肺、皮肤和头颈的鳞状癌（SCC），它们具有许多组织学和分子特征，共同构成了全球人类癌症的主要负担。相比之下，KRAS 是肺、胰腺和结肠腺癌中最常见的突变癌基因。在小鼠癌症模型中观察到相同的组织特异性：致癌物诱发的皮肤鳞状肿瘤几乎有 100% Hras 突变，而由相同致癌物诱发的肺腺癌几乎有 100% Kras 突变。识别这种特异性背后的因素将提供重要的信息，这些信息可能导致癌症预防或治疗的组织特异性或突变特异性途径。我们构建了新的小鼠模型，其中皮肤和肺中特定 Ras 亚型的特异性已被逆转或消除，导致小鼠出现 Kras 突变皮肤癌、Hras 突变肺癌，或对化学致癌剂治疗完全耐药。该项目将利用这些新型小鼠模型以及计算网络方法来识别正常组织和由 Hras 或 Kras 驱动的癌症中 Ras 基因的功能。小鼠基因表达网络数据将通过与来自肺癌和头颈鳞癌（由 TCGA 生成）或原发性皮肤 SCC 的人类基因表达数据集整合，在人类样本中进行验证，特别是来自接受 BRAF 抑制剂治疗的患者的人类 SCC HRAS (Q61L) 基因突变频率较高，与 Hras 突变小鼠皮肤肿瘤中发现的点突变完全相同。我们将使用系统生物学方法来可视化体内整个组织和突变小鼠上皮细胞中 Ras 信号传导的结构，以检查炎症与 Hras 或 Kras 驱动的恶性肿瘤发展易感性之间的关系。这种基于系统的综合方法将揭示鳞状癌形成的保守特征，这将首先帮助我们了解这些肿瘤的起源，并开始制定预防或治疗策略。