Validation and extension of an existing risk model for lung cancer

可靠的风险预测工具对估计肺癌（美国癌症死亡率的主要原因）概率的公共卫生影响是巨大的。在该提案中，我们建立在肺癌的流行病学风险模型的基础上，该模型是我们最近从1851名白人肺癌患者和2001名对照的肺癌病例对照研究中开发的，与来自父母资助的性别、年龄（± 5岁）、吸烟状况（目前、以前、从不）和种族的病例相匹配（ROl CA55679，P1：M. Spitz）。该风险模型还估计了个体患肺癌的绝对风险。使用本研究的独立数据集和大卫Christiani博士（合作研究者，哈佛公共卫生学院，CA 74386）的肺癌病例和对照的外部数据集，我们建议验证肺癌风险模型，并通过纳入风险的遗传生物标志物对其进行扩展。具体而言：1）。在800例前瞻性累积病例和800例对照中，使用父母资助的招募机制，我们将验证我们的原始模型，然后评估一种有前途的新型细胞遗传学生物标志物--微核阻断试验（CBMN）的额外区分能力，CBMN试验是一种多终点试验，不仅测量染色体损伤，（反映染色体断裂的微核;反映染色体重排的核质桥和反映基因扩增的核芽）以及其他细胞事件（凋亡和坏死）。我们将在基线和用烟草特异性亚硝胺NNK激发后测量这些终点。我们将推导出一种方法，将这些不同的染色体/遗传不稳定性措施整合到流行病学肺癌风险模型中。2）。利用目标1的发现，我们将构建一个扩展的风险模型，包括染色体不稳定性和基因-环境相互作用的措施。我们的初步数据表明，我们目前的模型具有中等的区分能力（70%），我们相信，将模型扩展到包括染色体不稳定性以及基因环境相互作用的这些生物标志物，只会提高我们的模型的区分能力。这种新开发的模型可能有助于识别高危人群，这些人群可以成为强化戒烟计划的目标，并可以参加化学预防筛选试验。3）。使用额外一组500例前瞻性入组的肺癌病例和500例对照（使用父母资助的招募机制）对原始和扩展肺癌风险模型进行内部验证，并比较扩展模型与原始Spitz模型之间的区分能力。这还将包括CBMN试验的独立内部验证。在独立样本中评价这些染色体终点将为随后将其他功能表型和基因型纳入模型提供原理证明。

The public health implications of reliable risk prediction tools for estimating the probability of lung cancer, the leading cause of cancer mortality in the US, are immense. In this proposal, we build upon an epidemiologic risk model for lung cancer that we recently developed from a lung cancer case-control study of 1851 Caucasian lung cancer patients and 2001 controls, matched to the cases on sex, age (±5 years), smoking status (current, former, never) and ethnicity from the parent grant (ROl CA55679, P1: M. Spitz). This risk model also estimates an individual's absolute risk for lung cancer. Using an independent data set from this study and an external data set of lung cancer cases and controls from Dr. David Christiani (co-investigator, Harvard School of Public Health, CA74386), we propose to validate the lung cancer risk model and extend it by incorporating a genetic biomarker of risk. Specifically: 1). In 800 prospectively accrued cases and 800controls using the recruitment mechanisms of parent grant, we will validate our original model and then assess the added discriminatory ability of a promising novel cytogenetic biomarker, the cytokinesis-block micronucleus (CBMN) assay, a multi-endpoint assay that measures not only chromosome damage (micronuclei reflecting chromosome breaks; nucleoplasmic bridges reflecting chromosome rearrangements and nuclear buds reflecting gene amplification) but also other cellular events (apoptosis and necrosis). We will measure these endpoints at baseline and following challenge with the tobacco-specific nitrosamine, NNK. We will derive a method to integrate these different measures of chromosome/genetic instability into the epidemiologic lung cancer risk model. 2). Using the findings from aim 1, we will construct an extended risk model to include measures of chromosome instability and gene-environment interactions. Our preliminary data show that our current model has moderate discriminatory power (70%), we believe that extending the model to includes these biomarkers of chromosome instability as well as gene environment interactions will only improve the discriminatory power of our model. This newly developed model may be useful to identify high-risk populations who could then be targeted for intensive smoking-cessation programs and could be enrolled into chemopreven-tion screening trials. 3). Internally validate the original and extended lung cancer risk models using an additional set of 500 prospectively enrolled lung cancer cases and 500 controls using the recruitment mechanisms of parent grant and compare the discriminatory power between the extended model to that of the original Spitz model between the two models. This will also include independent, internal, validation of the CBMN assay. Evaluation of these chromosomal endpoints in an independent sample will provide proof-of-principle for subsequent inclusion of additional functional phenotypes and genotypes into the model.