Validation and extension of an existing risk model for lung cancer

现有肺癌风险模型的验证和扩展

• 批准号: 7911887
• 负责人: RANDA A EL-ZEIN
• 金额: $ 61.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-12 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911887
• 关键词: 5 year old; Age; Apoptosis; Area; Biological Assay; Biological Markers; Cancer Center; Cancer Etiology; Cancer Family; Cancer Patient; Case-Control Studies; Caucasians; Caucasoid Race; Chemoprevention; Chromosomal Breaks; Chromosomal Instability; Chromosomes; Cytogenetics; Cytokinesis; DNA Sequence Rearrangement; Data; Data Set; Detection; Disease; End Point Assay; Enrollment; Epidemiology; Ethnic Origin; Evaluation; Event; Family history of; Gene Amplification; Genetic; Genotype; Goals; Health Benefit; Individual; Individual Differences; Intervention; Interview; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Medical History; Methods; Micronucleus Tests; Modeling; Necrosis; Nitrosamines; Nuclear; Occupational Exposure; Participant; Phenotype; Population; Predisposition; Probability; Public Health; Public Health Schools; ROC Curve; Research; Research Personnel; Risk; Sampling; Screening procedure; Smoking History; Smoking Status; Staging; Subgroup; Survival Rate; Tobacco; Validation; base; cancer risk; case control; design; gene environment interaction; high risk; improved; micronucleus; mortality; novel; parent grant; programs; sex; smoking cessation; tobacco carcinogenesis; tool

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.

用于估计肺癌概率的可靠风险预测工具对公共健康的影响是巨大的。肺癌是美国癌症死亡的主要原因。在这项建议中，我们建立了一个肺癌的流行病学风险模型，该模型是我们最近从1851名高加索肺癌患者和2001名对照的肺癌病例对照研究中开发的，与父母赠款(ROL CA55679，P1：M.Spitz)中的性别、年龄(±5岁)、吸烟状况(现在、以前、从未)和种族相匹配。该风险模型还估计了个人患肺癌的绝对风险。使用来自这项研究的独立数据集和来自David Christian博士(哈佛大学公共卫生学院CA74386共同研究员)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记物来扩展该模型。具体为：1)。在800个预期累积的病例和800个使用父母赠款招募机制的对照中，我们将验证我们的原始模型，然后评估一种有前景的新细胞遗传学生物标记物-胞质分裂阻断微核(CBMN)分析增加的区分能力，这是一种多终点分析，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)，而且还测量其他细胞事件(细胞凋亡和坏死)。我们将在基线和烟草特有的亚硝胺NNK挑战之后测量这些终点。我们将推出一种方法，将这些不同的染色体/遗传不稳定性测量方法整合到肺癌流行病学风险模型中。2)。利用目标1的发现，我们将构建一个扩展的风险模型，以包括染色体不稳定性和基因-环境相互作用的衡量标准。我们的初步数据显示，我们目前的模型具有中等的区分力(70%)，我们认为，将该模型扩展到包括这些染色体不稳定的生物标记物以及基因环境相互作用只会提高我们模型的区分力。这一新开发的模型可能有助于识别高危人群，这些高危人群随后可以成为强化戒烟计划的目标，并可以登记参加化疗预防筛查试验。3)。使用额外的500例预期登记的肺癌病例和500名对照，使用父母补助金的招募机制，在内部验证原始和扩展的肺癌风险模型，并比较扩展模型和原始Spitz模型之间的区分能力。这也将包括CBMN分析的独立的、内部的验证。对独立样本中这些染色体终点的评估将为随后将其他功能表型和基因类型纳入模型提供原则证明。