Combined Impact of Lifestyle, Dietary and Metabolic Factors on Colorectal Cancer Incidence and Survival in European Populations: Implications for Cancer Risk Assessment and Risk Prediction

结直肠癌（CRC）是世界范围内男性第三大常见癌症，女性第二常见癌症，近55%的病例发生在西欧等发达国家。迫切需要开发欧洲男性和女性结直肠癌的风险预测模型，以加强其预防。疾病频率与西化水平的平行表明，生活方式和代谢因素可能与结直肠癌的病因有关。越来越多的证据，包括来自欧洲癌症和营养前瞻性调查（EPIC）的数据表明，行为因素，如酒精、吸烟、体育活动、身体肥胖以及某些饮食和代谢因素都与结直肠癌的高风险相关。虽然这些因素的个别作用已被广泛研究，但对它们的共同作用知之甚少。然而，在现实生活中，人们很少采取孤立的行为；因此，多维数据分析方法对于探索疾病病因以及将流行病学发现转化为有意义的公共卫生信息将提供更多信息。通过这一应用，我们建议探讨生活方式、饮食和代谢因素组合对结直肠癌发病率和生存率的影响，并开发实用的结直肠癌风险评估和风险预测的公共卫生工具。具体而言，我们将利用对结直肠癌危险因素的先验知识，组成生活方式和代谢生物标志物指标，并探讨这些指标与结直肠癌发病率和生存率的关系。下一步，我们将开发一个CRC风险预测模型，并从其校准、识别和准确性方面评估该模型的性能。最后，我们将探讨新建立的生物标志物和遗传数据是否有可能改善已知结直肠癌危险因素之外的风险预测。拟议的分析将嵌入EPIC队列中，该队列包括519,928名年龄在25-70岁之间的男性和女性，他们提供了1992-2000年的饮食和生活方式信息、人体测量值和血液样本，并随访至2010年9月31日。在平均12年的随访中，确定了4,452例CRC病例（2,817例结肠，1,635例直肠）和1,107例CRC特异性死亡。该项目将利用EPIC队列的独特研究环境，并将受益于其强大的设计、大量病例和关于各种风险因素的高质量流行病学数据的可用性。本项目开发的风险预测模型最终可用于识别CRC的高风险人群和制定干预策略。因此，该项目有望对结直肠癌的临床一级预防和公共卫生产生直接影响。

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide with almost 55% of the cases occurring in developed countries, such as in Western Europe. Development of risk prediction models for CRC in European men and women is urgently needed to enhance its prevention. The parallel of disease frequency with the level of westernization points to the likely involvement of lifestyle and metabolic factors in the etiology of CRC. Mounting evidence, including data from the European Prospective Investigation into Cancer and Nutrition (EPIC) suggests that behavioral factors such as alcohol, smoking, physical activity, body fatness, and certain dietary and metabolic factors are individually related to a higher CRC risk. While individual roles of these factors have been extensively investigated, little is known about their joint effects. However, in real life it is uncommon that people practice isolated behaviors; therefore a multidimensional data analysis approaches would be more informative for exploring disease etiology, as well as for translating epidemiological findings into meaningful public health messages. With this application, we propose to explore the impact of combinations of lifestyle, dietary and metabolic factors on CRC incidence and survival, and to develop practical public health tools for CRC risk assessment and risk prediction. More concretely, we will use a-priori knowledge on CRC risk factors to compose lifestyle and metabolic biomarker indexes and explore associations of these indexes with CRC incidence and survival. As a further step, we will develop a CRC risk prediction model and evaluate the performance of this model in terms of its calibration, discrimination and accuracy. Finally, we will explore whether newly established biomarker and genetic data potentially improves risk prediction beyond known CRC risk factors. Proposed analyses will be embedded within the EPIC cohort comprising of 519,928 men and women, aged 25-70 years, who provided dietary and lifestyle information, anthropometric measurements and blood samples (1992-2000), and were followed up through September 31, 2010. Over a mean follow-up of 12 years, 4,452 incident CRC cases (2,817 colon, and 1,635 rectal) and 1,107 CRC-specific deaths were identified. The project will utilize the unique study setting of the EPIC cohort, and will profit from its strong design, large number of cases and availability of high-quality epidemiological data on variety of risk factors. The risk prediction model developed within this project could be ultimately used for identifying high risk groups and developing intervention strategies for CRC. Therefore, this project brings promises to be of direct impact for the primary prevention of CRC in clinical practice and public health.