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直肠癌和前列腺癌的营养和生化/遗传标志物研究。在过去的10年里，我们在胰岛素样生长因子（IGF）-I及其结合蛋白（IGFBP）-3、叶酸和MTHFR多态性、维生素D代谢物和维生素D受体（VDR）多态性以及致癌作用领域做出了重大贡献。我们计划在未来5年内采用前瞻性巢式病例对照研究设计，以这些发现为基础。具体而言，我们计划扩展IGF假说，以评估生长激素（GH）/IGF/胰岛素相关的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GH、酸不稳定亚基（ALS，循环中与IGF-I和IGFBP-3的三元复合物的第三组分）、C肽（胰岛素分泌的标志物）、瘦素（全身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性细胞因子）。我们还计划扩展叶酸假说，以评估维生素B6的主要活性形式吡哆醛5 '-磷酸（PLP）和同型半胱氨酸沿着一碳代谢途径在结直肠癌风险中的作用。我们将评估最近在关键GH/IGF-I/胰岛素信号通路、核激素受体和叶酸代谢通路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：GH 1、胰岛素受体底物（IRS）-1、IRS-2、磷脂酰肌醇3 '-激酶（PI 3 K）-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、甲硫氨酸合成还原酶（MTRR）和还原叶酸载体（RFC-1）。我们将评估这些多态性是否改变了循环中生化标志物水平与癌症风险的相关性。我们将探讨IGF-I，IGFBP-3和维生素D代谢物和VDR多态性之间的潜在相互作用。PHS起源于1982年，对14，916名提供基线血样的男性进行了20年的随访。1995年，我们从5,805名新参与者中收集了基线血液样本。我们总共预测了1,902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功效。已经收集了血液样本，并且已经对许多样本（直到2000年确定的病例和对照）的几种生化标志物（IGF-I、IGFBP-3、维生素D代谢物和叶酸）和多态性（VDR BsmI和MTHFR C677 T）进行了测定。因此，拟议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.