Cytokine Polymorphisms and Cancer Related Pain

描述(由申请人提供)： 疼痛是肺癌患者最具破坏性、持续性和致残性的症状之一。预测剧烈疼痛风险的能力是早期症状干预的基础。我们为一项旨在确定肺癌患者疼痛严重程度的流行病学和遗传预测因素的研究寻求资金。疾病相关变量、临床健康状况和社会人口学特征的影响仅能解释观察到的症状的微小差异。动物和人类的研究表明，细胞因子在疼痛生物学中发挥着重要作用。具体地说，脑内胶质细胞在体内释放促炎细胞因子后从头合成促炎细胞因子，已被证明促进和调节疼痛。癌细胞会异常地产生细胞因子。因此，我们假设免疫标记物(血浆细胞因子)的表达受细胞因子基因变异的调节，并且在有剧烈疼痛的患者和没有剧烈疼痛的患者中会有所不同。这项拟议的研究建立在M.D.安德森癌症中心所有阶段、年龄和组织学的原发肺癌患者的广泛数据和标本库的基础上，该研究来自NIH资助的一项研究(玛格丽特·斯皮茨，PI)，该研究收集了756名新诊断的、以前未经治疗的原发肺癌高加索白人患者的生物样本。在所有病例中，在任何癌症治疗之前，疼痛信息都是在基线上收集的。我们的初步数据(n=514)支持我们关于细胞因子基因(IL8)在疼痛严重程度中的重要作用的假说，最近已被接受发表。此外，通过父母的资助，已经可以获得一组关于炎症途径的基因分型数据。我们现在建议在这些令人信服的初步数据的基础上，通过测量血浆中关键细胞因子(IL-1a、IL-1β、IL1RN、IL-2、IL4、IL-6、IL-8、IL-10、TNF-a)的水平，并将选定的基因型与细胞因子水平相关联，以评估多态、细胞因子水平和疼痛严重程度之间的关联。其具体目标是：1)评估9个关键细胞因子基因(IL-1a、IL-1β、IL-1RN、IL-2、IL-4、IL-6、IL-8、IL-10、TNF-a)的多态发生率，并检测756例肺癌患者各组织学类型和分期的相关细胞因子的蛋白水平；2)基因分型与细胞因子水平的相关性；以及评估基因多态、细胞因子水平和疼痛程度之间的关系；以及3)利用先进的统计学方法建立包含生物学数据的统计风险模型，用于预测肺癌患者的疼痛严重程度；并通过检查接收器工作特性曲线下的区域和执行三重交叉验证来评估模型的预测性能。长期目标是开发定量的多变量风险评估模型，以确定将从早期疼痛干预中受益的患者亚群，并可能为癌症治疗选择提供信息。虽然近年来肺癌患者的存活率有所提高，但大多数患者仍然经历着痛苦和痛苦。了解宿主对剧烈疼痛的遗传易感性对于减轻癌症负担及其治疗至关重要。本研究结果具有重要的临床意义和公共卫生意义。

DESCRIPTION (provided by applicant): Pain is one of the most devastating, persistent and incapacitating symptoms in patients with lung cancer. The ability of predicting the risk for severe pain is fundamental for early symptom intervention. We seek funding for a study designed to identify epidemiologic and genetic predictors of pain severity in patients with lung cancer. The impact of disease-related variables, clinical health status and sociodemographic characteristics only account for a small variance observed in symptoms. Animal and human studies suggest an important role of cytokines in the biology of pain. Specifically, de novo synthesis of proinflammatory cytokines by glia in the brain in response to the release of proinflammatory cytokines in the body has been shown to facilitate and modulate pain. Cytokines are aberrantly produced by cancer cells. Accordingly, we hypothesize that expression profiles of immune markers (plasma cytokines) are modulated by variants in cytokine genes and will differ among patients with severe pain versus those without severe pain. The proposed study is built upon an extensive data and specimen repository of primary lung cancer patients of all stages, ages and histologies at M.D. Anderson Cancer Center, derived from an NIH-funded study (Margaret Spitz, PI) that has collected biologic samples on 756 White Caucasian patients with newly diagnosed, previously untreated primary lung cancer. In all cases, information on pain was collected at baseline, prior to any cancer treatment. Our preliminary data (n=514) supporting our hypothesis on the important role of cytokine genes (IL8) on pain severity have recently been accepted for publication. In addition, a panel of genotyping data on the inflammation pathway has become available through the parent grant. We now propose to build upon these compelling preliminary data by measuring plasma levels of key cytokines (IL-1a, IL-1¿, IL1RN, IL-2, IL4, IL-6, IL-8, IL-10, TNF-a) and correlating the select genotypes with cytokine levels to assess the association between polymorphisms, cytokine levels, and pain severity. The specific aims are: 1) To assess the prevalence of polymorphisms in 9 key cytokine genes (IL-1a, IL-1¿, IL-1RN, IL-2, IL4, IL-6, IL-8, IL-10, TNF-a) and to measure plasma protein levels of relevant cytokines in 756 patients of all histologies and stages of lung cancer; 2) To correlate genotype with cytokine levels; and assess the associations between polymorphisms, cytokine levels, and pain severity; and 3) To generate a statistical risk model incorporating biologic data for predicting the severity of pain in lung cancer patients using advanced statistical methods; and assess the predictive performance of the model by examining the areas under the receiver operating characteristic curves and performing three-fold cross validation. The long-term goal is to develop quantitative multivariate risk assessment models to identify patient subgroups that would benefit from early pain intervention and potentially inform cancer treatment options. Although improvements in the survival rates of patients with lung cancer have been observed in recent years, the majority of patients still experience distress and suffering. Understanding host genetic susceptibility to severe pain is critical to efforts in reducing the burden of cancer and its treatment. The results of this study have immense clinical and public health significance.