Nutritional and Biochemical/Genetic Markers of Cancer

描述（由申请人提供）：我们建议在医师健康研究（PHS）中扩展我们正在进行的结肠直肠癌和前列腺癌的营养和生化/遗传标记的研究。近10年来，我们在胰岛素样生长因子(IGF)- 1及其结合蛋白(IGFBP)-3、叶酸及其MTHFR多态性、维生素D代谢物和维生素D受体（VDR）多态性、致癌作用等领域做出了重要贡献。我们计划在未来5年使用前瞻性巢式病例对照研究设计来建立这些发现。具体来说，我们计划扩展IGF假说，以评估生长激素(GH)/IGF/胰岛素相关生化标志物在结直肠癌和前列腺癌中的作用。这些标志物包括生长激素、酸不稳定亚基（ALS，与igf - 1和IGFBP-3在循环中的三元复合物的第三个组成部分）、c肽（胰岛素分泌的标志物）、瘦素（总脂肪和能量平衡的标志物）、白细胞介素(IL)-6和c反应蛋白（CRP）（与肥胖和胰岛素抵抗相关的炎症细胞因子）。我们还计划扩展叶酸假说，以评估吡哆醛5'-磷酸（PLP），维生素B6的主要活性形式，以及沿单碳代谢途径的同型半胱氨酸在结直肠癌风险中的作用。我们将评估最近在关键的GH/IGF-I/胰岛素信号通路、核激素受体和叶酸代谢途径中发现的几种常见多态性的作用。这些包括编码以下蛋白质的基因多态性：GH1、胰岛素受体底物(IRS)-1、IRS-2、磷脂酰肌醇3′-激酶(PI3K)-p85亚基、过氧化物酶体增殖物激活受体（PPARgamma，一种在脂肪细胞分化中起关键作用的核激素受体）、VDR （FokI）、IL-6、蛋氨酸合成还原酶（MTRR）和叶酸载体（RFC-1）。我们将评估这些多态性是否会改变循环生化标志物水平与癌症风险的关系。我们将探索igf - 1、IGFBP-3与维生素D代谢物和VDR多态性之间的潜在相互作用。PHS始于1982年，对14916名提供基线血液样本的男性进行了20年的随访。1995年，我们收集了5805名新参与者的基线血液样本。我们共预测了1902例前列腺癌病例和369例结直肠癌病例，提供了相当好的统计能力。已经收集了血液样本，并对许多样本（2000年以前确定的病例和对照）进行了几种生化标记物（igf - 1、IGFBP-3、维生素D代谢物和叶酸）和多态性（VDR BsmI和MTHFR C677T）的分析。因此，拟议的项目具有很高的成本效益。

DESCRIPTION (provided by applicant): We propose to extend our on-going studies of nutritional and biochemical/genetic markers of colorectal and prostate cancer in the Physicians' Health Study (PHS). Over the past 10 years, we have made major contributions in the field of insulin-like growth factor (IGF)-I and its binding protein (IGFBP)-3, folate and the MTHFR polymorphism, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms and carcinogenesis. We plan to build upon these findings in the next 5 years using a prospective nested case-control study design. Specifically, we plan to extend the IGF hypothesis to assess the role of growth hormone (GH)/IGF/insulin-related biochemical markers in colorectal and prostate cancer. These markers include GH, acid labile subunit (ALS, a third component of the ternary complex with IGF-I and IGFBP-3 in circulation), C-peptide (a marker of insulin secretion), leptin (a marker of total body fat and energy balance), interleukin (IL)-6 and C-reactive protein (CRP) (inflammatory cytokines linked to obesity and insulin resistance). We also plan to extend the folate hypothesis to assess the role of pyridoxal 5'-phosphate (PLP), the principal active form of vitamin B6, and homocysteine along the one-carbon metabolism pathway in risk of colorectal cancer. We will evaluate the roles of several common polymorphisms recently identified in the key GH/IGF-I/insulin signaling pathway, in nuclear hormone receptors, and in the folate metabolic pathway. These include polymorphisms in genes encoding the following proteins: the GH1, insulin receptor substrate (IRS)-1, IRS-2, posphatidylinositol 3'- kinase (PI3K)-p85 subunit, peroxisome proliferator-activated receptor (PPARgamma, a nuclear hormone receptor that plays a key role in adipocyte differentiation), VDR (FokI), IL-6, methionine syntheses reductase (MTRR), and reduced folate carrier (RFC-1). We will evaluate whether these polymorphisms modify the associations of circulating levels of biochemical markers with cancer risk. We will explore potential interactions between IGF-I, IGFBP-3 and vitamin D metabolites and VDR polymorphisms. The PHS originated in 1982 with two decades of follow-up of 14,916 men who provided blood samples at baseline. In 1995, we collected a baseline blood sample from 5,805 new participants. We project a total of 1,902 prostate cancer cases, and 369 colorectal cancer cases, providing reasonably good statistical power. The blood samples are already collected, and several biochemical markers (IGF-I, IGFBP-3, vitamin D metabolites, and folate) and polymorphisms (VDR BsmI and MTHFR C677T) are already assayed for many of the samples (cases and controls identified up to 2000). Hence, the proposed project is highly cost-efficient.