One-carbon metabolism biomarkers and lung cancer risk

描述(由申请人提供)：我们最近在欧洲前瞻性研究和癌症(EPIC)队列中，基于从900名患者和1800名对照人群中前瞻性收集的血液样本，发现一碳代谢(OCM)的循环生物标记物与肺癌之间存在强烈的相关性。这项研究强烈暗示了维生素B6和蛋氨酸的重要保护作用，与吸烟状态无关，导致这两种维生素措施加在一起的最高和最低25%人群的风险差异是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。这项扩大的研究的主要目标有两个：i)在一个足够大的研究人群中，澄清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，以允许使用分子流行病学和遗传学方法进行按吸烟状况分层的强有力的风险分析，以及ii)在多个队列中衡量OCM生物标记物在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患者的血液样本。这项研究将包括在美国/欧洲/澳大利亚队列中招募的1200对从未吸烟、以前吸烟和现在吸烟的病例对照对，以及在亚洲队列中招募的1500对病例对照对。我们还将包括来自一个小组的1000个重复样本，以校正回归稀释偏差，从而对11,200个血清/血浆样本进行生化分析。将在整个研究人群中测量多达40个单碳代谢生物标记物的循环水平，我们将量化它们与后续肺癌风险的关系。对先验兴趣的重要分析将包括分别测量从不吸烟者和曾经吸烟者与风险的关联。这些风险估计随后将用于风险预测模型，还将考虑回归稀释。来自EPIC队列的初步数据表明，血清蛋氨酸和维生素B6的测量可能会发现肺癌终生风险的差异高达7倍。肺癌仍然是世界范围内的主要健康问题，占美国所有癌症死亡人数的28%。除了阐明OCM生物标记物与肺癌之间的联系外，这一倡议还将创建更详细的风险预测模型，而不仅仅是烟草暴露的详细信息。建立该联盟的重要工作也将带来启动关于肺癌病因学的更多研究的机会。

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.