Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study

ATBC队列随访研究自1994年开始。1985年4月至1988年6月，研究人员从芬兰西南部招募了年龄在50岁至69岁之间的男性吸烟者。共有29133名男性被随机分配到四个干预组：50毫克/天的A -生育酚（dl- A -生育酚乙酸酯）；b-胡萝卜素20毫克/天；a-生育酚和b-胡萝卜素；或安慰剂。在试验期间对他们进行了5至8年的随访，直到死亡或1993年4月30日停止干预（中位随访时间为6.1年）。在通过基于人群的邮政调查邀请参与和招募后，该试验随机将29,133名50-69岁男性高加索吸烟者分配到基于2x2因子设计的四个干预组之一：-胡萝卜素（20毫克/天），维生素E（50毫克/天，作为dl-生育酚乙酸酯），两种药物或安慰剂。在入职时，获得了医疗、饮食、吸烟和职业数据，以及物理测量、胸部x光检查、血清和脚趾甲样本。饮食是通过一份276种食物的饮食问卷来记录的，该问卷是为试验开发和验证的。收集、冷冻并保存所有参与者的基线血清，并测定维生素E、β -胡萝卜素、视黄醇、总胆固醇和高密度脂蛋白胆固醇。在研究后期收集所有活跃参与者的随访血清和全血，以及从选定的亚群中收集额外的血清和红细胞样本。积极干预持续了5-8年，每年进行三次研究访问，在此期间，参与者被问及自上次访问以来他们的健康状况和可能的主观副作用、胶囊依从性和吸烟习惯。每隔2-3年和试验结束时拍摄胸片。通过芬兰全国癌症登记处确定了所有癌症事件，审查了医疗记录/病理切片/摘要，并通过国家人口登记册确定了死亡/潜在原因。ATBC队列随访研究的总体目标是在29133名男性的原始试验队列基础上进行癌症病因学研究和干预后癌症监测。队列分析、巢式病例对照调查、遗传多态性和其他分子参数分析以及干预剂对相关生物标志物的生物学效应研究已经开展，并且是正在进行的研究重点。截至2005年，目前确诊病例的累计总数包括约2800例肺癌、2000例前列腺癌、700例结肠直肠癌、500例膀胱癌、300-400例胃癌、胰腺癌和肾癌、300例头颈癌和1100例其他肿瘤。ATBC研究中的癌症病因学研究已经自然地从关注补充剂发展到几个集中领域，这些领域反映了我们的研究兴趣和研究资源的可用性，以满足NCI和其他地方不断增长的高生产力研究人员的需求。一个公共网站（http://dceg.cancer.gov/atbcstudy）提供有关项目、研究、数据、人员和资源的信息，包括启动合作的程序。高质量的研究数据、生物标本和正在进行的终点确定已被应用于测试与前列腺癌（2500例）、肺癌（3500例）、结直肠癌（700例）、胰腺癌（400例）和其他癌症中具有潜在高归因风险的营养和其他因素相关的生化和遗传学假设。GWAS对前列腺癌、肺癌、肾癌和膀胱癌以及非霍奇金淋巴瘤和神经胶质瘤的风险研究已经完成。我们已经完成了对维生素D、E、A和硒的调查；类胡萝卜素和其他抗氧化剂；一个碳代谢;能量平衡、胰岛素和生长因子；性类固醇;以及影响这些暴露的基因变异。正在进行营养表型（如血清维生素D状态）的GWAS研究。在控制维生素补充设计的背景下评估这些因素为我们研究生物和生化相互作用提供了独特的机会。ATBC研究的另一个重要方面是与癌症流行病学协会的校外研究人员合作。这些包括：NCI乳腺癌和前列腺癌队列联盟（BPC3）、PanScan、饮食和癌症前瞻性研究汇集项目，以及哈佛大学叶酸、单碳营养素、基因变异和结直肠癌专业中心。我们为这些强大的、高影响力的研究提供科学专业知识、数据和队列资源以及内部支持。

The ATBC Cohort Follow-up Study has been in place since 1994. Male smokers between the ages of 50 and 69 were recruited from southwestern Finland between April 1985 and June 1988. A total of 29,133 men were randomly assigned to one of four intervention groups: 50 mg/day a-tocopherol (as dl-a-tocopheryl acetate); 20 mg/day b-carotene; both a-tocopherol and b-carotene; or placebo. They were followed for five to eight years during the trial, until death, or 30 April 1993 when intervention was stopped (median follow-up, 6.1 years). Follow-up for endpoints was continued postinterventionFollowing invitation for participation and recruitment through a population-based postal survey, the trial randomly assigned 29,133 Caucasian 50-69 year old male smokers of >5 cigarettes daily to one of four intervention groups based on a 2x2 factorial design: -carotene (20 mg/day), vitamin E (50 mg/day, as dl--tocopheryl acetate), both agents, or placebo. At entry, medical, dietary, smoking, and occupational data were obtained, along with physical measurements, a chest x-ray, and serum and toenail samples. Diet was captured through a 276 food item dietary questionnaire that was developed and validated for the trial. Baseline serum was collected, frozen, and stored for all participants, and vitamin E, beta-carotene, retinol, and total and HDL cholesterol were determined. Follow-up serum and whole blood were collected for all active participants later in the study, as were additional serum and red blood cell samples from selected subsets. Active intervention continued for 5-8 years, with three study visits annually during which participants were asked about their health and possible subjective side effects, capsule compliance, and smoking habits since the last visit. Chest films were taken at 2-3 year intervals and at the end of the trial. All incident cancers were identified through the nationwide Finnish Cancer Registry, medical records/pathology slides were reviewed / abstracted, and deaths/underlying causes were identified through the National Population Register. The ATBC Cohort Follow-up Study has had the overall aim of conducting cancer etiologic research and post-intervention cancer surveillance based on the original trial cohort of 29,133 men. Cohort analyses, nested case-control investigations, analyses of genetic polymorphisms and other molecular parameters, and studies of the biological effects of the intervention agents on relevant biomarkers have been conducted and are the focus of ongoing research. Current cumulative totals of diagnosed cases through 2005 include approximately 2,800 lung, 2,000 prostate, 700 colorectal, 500 bladder, 300-400 each for stomach, pancreas, and kidney cancers, 300 head and neck, and 1,100 for other sites combined. Cancer etiologic research in the ATBC Study has evolved naturally from the focus on supplementation into several areas of concentration that reflect both our research interests and the availability of study resources to a continually growing number of highly productive investigators both at NCI and elsewhere. A public website (http://dceg.cancer.gov/atbcstudy) provides information regarding the projects research, data, personnel, and resources, including procedures for initiating collaborations. The high-quality study data, biological specimens, and ongoing endpoint ascertainment have been applied to testing biochemical and genetic hypotheses related to nutritional and other factors having potentially high attributable risks in prostate (based on 2,500 cases), lung (3,500 cases), colorectal (700 cases), pancreatic (>400 cases) and other cancers. GWAS studies of risk for prostate, lung, renal, and bladder cancers, as well as NHL and glioma are completed. We have completed investigations of vitamins D, E, A and selenium status; carotenoids and other antioxidants; one-carbon metabolism; energy balance, insulin, and growth factors; sex steroids; and genetic variants impacting these exposures. GWAS studies of nutrition phenotypes such as serum vitamin D status are being conducted. Evaluation of these factors within the context of the controlled vitamin supplementation design has afforded us unique opportunities to investigate biological and biochemical interactions. Another important dimension of the ATBC Study has been collaborations with extramural researchers in cancer epidemiological consortia. These include: the NCI Breast and Prostate Cancer Cohort Consortium (BPC3), PanScan, the Pooling Project of Prospective Studies of Diet and Cancer, and the Harvard Specialized Center on Folate, One-Carbon Nutrients, Gene Variants and Colorectal Cancer. We contribute scientific expertise, data and cohort resources, and intramural support to these powerful, high-impact studies.