Genetic analysis of ras mutation specificity in skin and lung cancer

描述(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基因突变。这些肿瘤特别难治疗，而且预后非常差。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别RAS亚型特定突变的细胞。HRAS基因突变主要见于肺鳞癌、皮肤鳞癌和头颈部鳞癌，它们具有许多共同的组织学和分子特征，共同构成了全球主要的人类癌症负担。相比之下，KRAS是肺癌、胰腺癌和结肠癌中最常见的突变癌基因。在小鼠癌症模型中也观察到了同样的组织特异性：致癌物诱导的皮肤鳞癌几乎有100%的HRAS突变，而同一致癌物诱导的肺腺癌几乎有100%的Kras突变。识别这种特异性的基础因素将提供重要的信息，这些信息可能导致组织特异性或突变特异性的癌症预防或治疗途径。我们建立了新的小鼠模型，其中皮肤和肺中特定RAS亚型的特异性已被逆转或消除，导致小鼠患上Kras突变皮肤癌、HRAS突变肺癌或对化学致癌物治疗完全耐药。该项目将利用这些新的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肺部和头颈部鳞癌(由TCGA生成)或原发皮肤SCC的人类基因表达数据集整合在人类样本中得到验证，尤其是与来自BRAF抑制剂治疗患者的人类SCC整合，这些患者具有更高的HRAS(Q61L)基因突变频率-与在HRAS突变的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的方法来可视化体内整个组织和来自突变小鼠的上皮细胞中RAS信号的架构，以检查炎症与HRAS或KRAS驱动的恶性肿瘤发生的易感性之间的关系。这种基于系统的综合方法将揭示鳞癌形成的保守特征，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。

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.