One-carbon metabolism biomarkers and lung cancer risk

描述（由申请人提供）：我们最近基于从900例病例和1，800例对照中前瞻性收集的血液样本，在欧洲前瞻性研究和癌症（EPIC）队列中确定了一碳代谢（OCM）循环生物标志物与肺癌之间的强相关性。该研究强烈暗示维生素B6和蛋氨酸的重要保护作用与吸烟状况无关，导致这些维生素措施组合的最高和最低25%人群之间的风险差异为2.5倍（p=10-12）。重复测量表明，由于回归稀释，这些影响被大大低估。这项扩展研究的主要目的有两个方面：i）在足够大的研究人群中阐明B族维生素和相关因素（单碳代谢途径）在肺癌病因学中的作用，以便使用分子流行病学和遗传学方法进行按吸烟状态分层的稳健风险分析，ii）测量OCM生物标志物在多个队列中肺癌风险预测中的作用。我们与参与NCI队列联盟的20多个队列合作发起了一个肺癌联盟，包括总共11，500例前瞻性收集的肺癌病例和血液样本。本研究将包括在美国/欧洲/澳大利亚队列中招募的1，200例从未吸烟、既往吸烟和当前吸烟的病例对照对，以及在亚洲队列中招募的1，500例病例对照对。我们还将纳入来自亚组的1，000份重复样本，以校正回归稀释偏倚，从而对11，200份血清/血浆样本进行生化分析。将在整个研究人群中测量多达40种一碳代谢生物标志物的循环水平，并量化它们与随后肺癌风险的相关性。先验利益的重要分析将包括分别测量从不吸烟者和既往吸烟者之间的风险关联。这些风险估计随后将用于风险预测模型，同时考虑到回归稀释。来自EPIC队列的初步数据表明，蛋氨酸和维生素B6的血清测量可以识别肺癌终生风险的7倍差异。肺癌仍然是世界范围内的主要健康问题，并且占美国所有癌症死亡的28%。除了阐明OCM生物标志物与肺癌之间的关联外，该倡议还将创建更详细的风险预测模型，超过仅烟草暴露的详细信息所提供的模型。该联盟的重要工作也将为启动有关肺癌病因学的其他研究提供机会。

DESCRIPTION (provided by applicant): We have recently identified strong associations between circulating biomarkers of one-carbon metabolism (OCM) and lung cancer within the European Prospective Investigation and Cancer (EPIC) cohort, based on prospectively collected blood samples from 900 cases and 1,800 controls. The study strongly implicated important protective effects for both vitamin B6 and methionine independently of smoking status, resulting in 2.5-fold risk differences between the top and bottom 25% of the population for these vitamin measures combined (p=10-12). Repeat measures indicated that these effects were substantially under-estimated because of regression dilution. The main objectives of this expanded study are two-fold: i) to clarify the role of B-vitamins and related factors (the one-carbon metabolism pathway) in lung cancer etiology in a study population large enough to allow robust risk analyses stratified by smoking status, using both molecular epidemiology and genetic approaches, and ii) to measure the role of OCM biomarkers in lung cancer risk prediction in multiple cohorts. We have initiated a lung cancer consortium in collaboration with over 20 cohorts participating in the NCI Cohort Consortium, including in total 11,500 prospectively collected lung cancer cases with blood samples. This study will include equal proportions of 1,200 never, former, and current smoking case-control pairs recruited in US/European/Australian cohorts, as well as 1,500 case-control pairs recruited in Asian cohorts. We will also include 1,000 repeat samples from a subgroup to allow for correction of regression dilution bias, resulting in biochemical analysis of 11,200 serum/plasma samples. Circulating levels of up to 40 biomarkers of one-carbon metabolism will be measured in the whole study population, and we will quantify their association with subsequent lung cancer risk. Important analyses of a priori interest will include measuring the association with risk among never and former smokers separately. These risk estimates will subsequently be used in risk prediction models, also taking regression dilution into account. Preliminary data from the EPIC cohort indicate that serum measures of methionine and vitamin B6 may identify up to 7-fold differences in life-time risk of lung cancer. Lung cancer remains a major health problem world-wide, and is responsible for 28% of all cancer deaths in the US. As well as elucidating the association between OCM biomarkers and lung cancer, this initiative will create more detailed risk prediction models, over and above that afforded by detailed information on tobacco exposure alone. The important work that will go into the construction of this consortium will also result in opportunities to initiate additional studies concerning lung cancer etiology.