DIET, HORMONES, AND RISK OF COLORECTAL CANCER

在美国，结直肠癌是癌症死亡的第二大原因。如果不采取预防措施， 大约6%的美国人会在有生之年患上这种恶性肿瘤。在过去的几十年里，有 在我们对结直肠癌发生的三个致病途径的理解上取得了重大进展：DNA 影响基因表达和基因组稳定性的甲基化异常、胰岛素和胰岛素样生长因子(IGF) 信号，它影响细胞的增殖和凋亡，以及炎症。许多拟议的可修改因素 结直肠癌(叶酸、维生素B-6和维生素B-12摄入量低、酒精摄入量高、体重超标、 久坐的生活方式、钙摄入量和维生素D水平以及不使用阿司匹林)可能通过这些途径起作用。我们 建议前瞻性和广泛地研究这些可改变的因素如何影响结直肠癌风险 通过这三条途径运作。我们将利用来自护士健康研究的数据，这是一项正在进行的大型前瞻性研究 对女性的研究。我们将利用(1)30年来积累的多份问卷来研究相关暴露 评估长期暴露的影响，包括饮食，(2)营养和激素生物标记物，以及(3)遗传因素 与感兴趣的路径相关。这些暴露和遗传因素将根据不同的终点进行检查。 包括(1)总的结直肠癌发病率，(2)结直肠癌的特定分子改变(包括CpG 岛甲基化，hMLHt，O6-甲基鸟嘌呤-DNA甲基转移酶，p16K和p27，以及 磷酸化Akt和COX-2的过度表达)和(3)结直肠癌根治性切除后的生存率 癌症，占了已知的预后因素后，这种疾病。通过更好地理解潜在的机制， 剂量-反应关系，作用于相似途径的因子之间的相互关系(例如，叶酸和维生素B-6、胰岛素和 IGF-1)，遗传易感性引起的反应变化，以及与特定肿瘤标记物的相关性的特异性 加强因果关系的理由，我们可以巩固和完善旨在减少发病率和死亡率的建议 从这种基本上可以预防的癌症中。

Colorectal cancer is the second leading cause of cancer death in the United States. Without preventive actions, approximately 6% of Americans will develop this malignancy during their lifetime. In the past several decades, there have been major developments in our understanding of three pathogenic pathways for colorectal carcinogenesis: DNA methylation aberrations, which affect gene expression and genomic stability, insulin and insulin-like growth factor (IGF) signaling, which influences cell proliferation and apoptosis, and inflammation. Many of the proposed modifiable factors for colorectal cancer (low intakes of folate, vitamin B-6 and vitamin B-12, high alcohol intake, excess body weight, sedentary lifestyle, calcium intake and vitamin D levels, and non-use of aspirin) may operate through these pathways. We propose to examine prospectively and extensively how these modifiable factors may influence colorectal cancer risk operating through these three pathways. We will utilize data from the Nurses' Health Study, a large ongoing prospective study of women. We will study relevant exposures utilizing (1) multiple questionnaires accumulated over 30 years to assess the influence of long-term exposures including diet, (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant to the pathways of interest. These exposures and genetic factors will be examined in relation to various endpoints including (1) total colorectal cancer incidence, (2) specific molecular alterations in colorectal cancer (including CpG island methylation, loss of expression of hMLHt, O6-methylguanine-DNA methyltransferase, p 16K and p27, and overexpression ofphospho-Akt and COX-2), and (3) survival from colorectal cancer following a curative resection of this cancer, after accounting for know prognostic factors for this disease. By better understanding underlying mechanisms, dose-response relations, inter-relations among factors acting in similar pathways (e.g. folate and vitamin B-6, insulin and IGF-1), variation in response due to genetic susceptibility, and specificity in associations to specific tumor markers which enhances the case for causality, we can solidify and refine recommendations aimed at reducing the incidence and mortality from this largely preventable cancer.