Genetic analysis of ras mutation specificity in skin and lung cancer

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，预后很差。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个体RAS亚型中携带特定突变的细胞的早期选择。HRAS基因突变主要见于肺、皮肤和头颈部的鳞状癌（SCCs），它们具有许多组织学和分子特征，共同构成了世界范围内主要的人类癌症负担。相反，KRAS是肺、胰腺和结肠腺癌中最常见的突变癌基因。在小鼠癌症模型中也观察到相同的组织特异性：致癌物诱导的皮肤鳞状肿瘤几乎100%发生Hras突变，而由相同致癌物诱导的肺腺癌几乎100%发生Kras突变。确定这种特异性背后的因素将提供重要的信息，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亚型的特异性被逆转或消除，导致小鼠发生Kras突变型皮肤癌，Hras突变型肺癌，或对化学致癌物质治疗完全耐药。该项目将利用这些新的小鼠模型以及计算网络方法来鉴定Ras基因在正常组织和由Hras或Kras驱动的癌中的功能。小鼠基因表达网络数据将在人类样本中通过整合来自肺癌和头颈部鳞状癌（由TCGA产生）或原发性皮肤SCCs的人类基因表达数据集进行验证，特别是来自braf抑制剂治疗的患者的人类SCCs，这些患者的HRAS （Q61L）基因突变频率升高-与在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来自突变小鼠的上皮细胞中的Ras信号结构，以检查炎症与Ras或kras驱动的恶性肿瘤发展易感性之间的关系。这种全面的基于系统的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发生，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.