Integrative Genetics of Cancer Susceptibility

描述（由申请人提供）： 拟议的研究将建立在我们最近对遗传网络的研究基础上。我们将扩展这些，最初强调结肠癌和乳腺癌，包括血清，尿液和其他生理分析，以开发“癌症易感状态”的模型，以建立更好的小鼠模型来研究癌症易感性和个体遗传组成和环境暴露影响易感性和最终治疗反应的机制。我们对癌症易感性状态的定义将借鉴用于定义RNA和蛋白质表达的高通量方法以及用于定义控制该表达的基因的高通量方法。我们还将解决癌症研究中的几个关键问题，包括饮食如何影响与癌症易感性相关的遗传网络，肥胖在促进癌症易感性中的作用，环境暴露与遗传诱导的差异等。这项研究无疑是癌症研究的一个新范式，应该会导致新的易感性生物标志物，更好地理解有助于癌症易感性的中间表型，以及生物可塑性和网络转换在癌症易感性中的作用，并直接应用于人类生物学。

DESCRIPTION (provided by applicant): The proposed studies will build upon our recent research into genetic networks. We will be extending these, with an initial emphasis on colon and breast cancer, to include serum, urine, and other physiological analyses to develop models of a 'cancer susceptibility state' in order build better mouse models to investigate cancer predisposition and the mechanism by which an individuals genetic makeup and environmental exposure influences susceptibility and eventual response to therapy. Our definition of the cancer susceptibility state will draw from high-throughput methods for defining RNA and protein expression and high-throughput methods for defining genes that control that expression. We will also be addressing several critical issues in cancer research including how diet influence genetic networks associated with cancer susceptibility, the role of obesity in contributing to cancer susceptibility, how environmental exposures differ from genetic induction, among others. This research is definitely a new paradigm for cancer research and should lead to new biomarkers for susceptibility, a better understanding of intermediate phenotypes contributing to cancer susceptibility, and the role of biological plasticity and network switching in cancer predisposition with direct applications to human biology.