Polymorphisms of INS/IGF Signal Pathways & Female Cancer

描述（由申请人提供）：乳腺癌、结直肠癌和子宫内膜癌是美国女性的4大主要癌症部位之一。虽然与这些癌症相关的环境因素已得到很好的研究，但其潜在的遗传机制尚不清楚。易感基因的鉴定对于理解这些癌症的生物学基础是重要的。这项拟议的研究将被纳入一项正在进行的NIH资助的病例队列研究，该研究在妇女健康倡议（WHI）中进行，这是一项针对绝经后妇女的大型前瞻性研究。正在进行的病例队列研究旨在测量900例乳腺癌、500例结直肠癌和300例子宫内膜癌病例以及900例受试者的子队列中胰岛素、IGF-I、IGFBP-3和雌二醇的血清水平，并检查其对3种癌症风险的影响。本文提出的研究将在相同的研究对象中在遗传水平上检查胰岛素/IGF系统。研究胰岛素/IGF系统有以下几个原因：（1）它对细胞增殖和转化具有重要的调节作用。(2)血清胰岛素/IGF水平与几种癌症的风险有关。(3)它与乳腺癌相关的癌症特别相关，因为胰岛素，IGF-I和雌二醇增强彼此的信号作用。在这些基础上，假设参与胰岛素/IGF信号传导的基因的变化可能导致这些生长因子的生物学效应和/或血清水平的改变，并且这些基因可能影响癌症的易感性。本研究的目的是：（1）确定参与胰岛素/IGF信号传导的9个基因（即PI 3 K和MAPK通路）的遗传变异，并检查其与乳腺癌、结直肠癌和子宫内膜癌风险的关系。(2)在子队列中检查遗传变异是否与胰岛素、IGF-I和IGFBP-3的血清水平改变相关。(3)在癌症病例中确定这些基因的变异是否与诊断特征相关。本研究的第二个目的是探讨雌二醇和这些基因的变异对这三种癌症风险的交互作用。利用WHI现有的DNA样本，本研究将采用最新的遗传分析方法来评估3种癌症的候选基因。这项遗传学研究，结合正在进行的血清学研究，将提供一个全面的检查胰岛素/IGF系统在肿瘤发生中的作用。

DESCRIPTION (provided by applicant): Breast, colorectal, and endometrial cancers are among the top 4 leading cancer sites in women in the U.S. While environmental factors associated with these cancers have been well studied, the underlying genetic mechanisms are not well understood. The identification of susceptibility genes is important for understanding the biological basis of the causes of these cancers. This proposed study will be integrated in an ongoing NIH-funded case-cohort study conducted within the Women's Health Initiative (WHI), a large prospective study of postmenopausal women. The ongoing case-cohort study aims to measure serum levels of insulin, IGF-I, IGFBP-3, and estradiol in 900 breast, 500 colorectal, and 300 endometrial cancer cases and a sub-cohort of 900 subjects and to examine their effects on risk of the 3 cancers. The study proposed here will examine the insulin/IGF system at the genetic level in the same study subjects. There are several reasons to focus on the insulin/IGF system: (1) It has significant regulatory effects on cell proliferation and transformation. (2) Serum levels of insulin/IGF are associated with risk of several cancers. (3) It is particularly relevant to the hormone-related cancers, since insulin, IGF-I, and estradiol potentiate each other's signaling effects. On these bases, it is hypothesized that variations in the genes involved in insulin/IGF signaling may lead to altered biological effects and/or serum levels of these growth factors, and these genes could influence the susceptibility of cancer. The objectives of this study are: (1) To identify genetic variation in 9 genes that are involved in insulin/IGF signaling, namely the PI3K and MAPK pathways, and to examine their associations with risks of breast, colorectal, and endometrial cancer. (2) To examine in the subcohort if the genetic variation is associated with altered serum levels of insulin, IGF-I, and IGFBP-3. (3) To determine among the cancer cases if variation in these genes are associated with diagnostic characteristics. The secondary objective of this study is to explore the interactive effects between estradiol and variation of these genes on risk of the 3 cancers. Using existing DNA samples from the WHI, this study will apply the latest genetic analytical approach to evaluate candidate genes of 3 cancers. This genetic study, in conjunction with the ongoing serological study, will provide a comprehensive examination of the role of the insulin/IGF system in tumorigenes