Inflammation Genes and Lung Cancer Risk

炎症基因和肺癌风险

基本信息

批准号：
8506981
负责人：
MARGARET R SPITZ
金额：
$ 19.25万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506981
关键词：
Adopted Affect Age Algorithms Anti-Inflammatory Agents Anti-inflammatory Antihistamines Apoptosis Area Asbestos Asthma Base Excision Repairs Bioinformatics Biological Assay Biology Caucasians Caucasoid Race Cell Cycle Cell Cycle Regulation Characteristics Chronic Chronic Obstructive Airway Disease Complex Computer Simulation DNA DNA Repair DNA Repair Pathway Data Data Set Development Dietary intake Disease Drug usage Dust Enrollment Environment Epidemiology Ethnic Origin Family Cancer History Family history of Frequencies Gender Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype Goals Growth Factor Haplotypes Hay fever Host Defense In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury International Irritants Joints Letters Life Link Literature Logistic Regressions Lymphocyte Machine Learning Malignant Neoplasms Malignant neoplasm of lung Maps Medical History Metabolism Modeling Molecular Molecular Biology Nature Newly Diagnosed Non-Small-Cell Lung Carcinoma Not Hispanic or Latino Nucleotide Excision Repair Occupational Exposure Outcome Oxidative Stress Participant Pathway interactions Phenotype Physicians Play Predisposition Probability Process Progress Review Group Proxy Public Health Publishing Pulmonary Emphysema Receiver Operating Characteristics Recommendation Recording of previous events Recruitment Activity Regression Analysis Research Resources Respiratory System Respiratory tract structure Risk Risk Factors Role Smoking Smoking Behavior Smoking History Smoking Status Specimen Staging Structure of parenchyma of lung Testing Tissues Training Validation Variant aggregation pathway angiogenesis base cancer risk cancer site carcinogenesis case control cell growth chemical property cigarette smoking gene interaction genetic variant medical specialties meetings novel parent grant public health relevance repository response tool tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): There is accumulating evidence that chronic injury and inflammation in the respiratory tract, such as that caused by cigarette smoking, predispose to lung cancer. We therefore propose to conduct an in depth pathway-based analysis of gene variants in the inflammatory pathway using test and validation sets of cases and controls. This proposal builds on a well-annotated specimen repository of lung cancer cases and controls enrolled in an ongoing risk factor study (CA55769, Spitz, PI). Cases are frequency-matched to controls on age, gender, ethnicity and smoking status recruited from a multi-specialty physician practice. Data collected include smoking history, dietary intake, cancer family history, specific occupational exposures (e.g., asbestos, dust), and previous medical history including chronic obstructive airway disease, asthma and hay fever. Genomic DNA and rich candidate genotype and phenotype data are available. Aim 1: To identify novel genetic variants influencing lung cancer risk in a test set of 1500 cases with non-small cell lung cancer and 1500 matched controls (all Caucasian), using the Illumina iSelect Infinium chip with 8.5 to 9K SNP's. Aim 2: In a replication set of an additional 1000 cases and 1000 controls, using a GoldenGate assay, we will evaluate the top 1500 SNPs identified from Aim1 as meeting the P<0.1 criterion, or selected by a rational prioritizing approach that incorporates published results, type of SNP, evolutionary biology, physico-chemical properties and haplotype tagging SNPs. Aim 3: To perform fine mapping in the flanking regions of 50 SNPs selected by the same approach as in Aim 2, combining prior information with in silico approaches for predicting functionality. For each of these 50 SNPs, we will select an average of 10 additional SNPs per gene region to regenotype in all 2500 cases and 2500 controls. Aim 4. To extend our epidemiologic risk prediction model by incorporating established epidemiologic risk factor and gene variant data. We will apply machine-learning tools to identify gene-environment and gene-gene interactions. Covariates will include prior emphysema, asthma, hay fever, dust and asbestos exposure, smoking characteristics, family history of cancer, and anti-inflammatory drug use. The International Lung Cancer Consortium will perform external validation in a proposal to be developed. Our approach to comprehensively evaluate variants in a candidate pathway in a large well- powered study will be applicable to a variety of other cancer sites where inflammation plays an important etiologic role, as well as in non-neoplastic diseases with a strong inflammatory component such as emphysema. The public health potential of a useful risk prediction modes for lung cancer is substantial.

描述（由申请人提供）：越来越多的证据表明，呼吸道的慢性损伤和炎症（例如吸烟引起的损伤和炎症）容易患肺癌。因此，我们建议使用病例和对照的测试和验证集对炎症途径中的基因变异进行深入的基于途径的分析。该提案建立在一个注释明确的肺癌病例和对照样本库的基础上，该样本库参与了一项正在进行的危险因素研究（CA55769，Spitz，PI）。病例与从多专业医师诊所招募的年龄、性别、种族和吸烟状况的对照进行频率匹配。收集的数据包括吸烟史、饮食摄入量、癌症家族史、特定职业暴露（例如石棉、灰尘）以及既往病史，包括慢性阻塞性气道疾病、哮喘和花粉热。可以获得基因组 DNA 和丰富的候选基因型和表型数据。目标 1：使用具有 8.5 至 9K SNP 的 Illumina iSelect Infinium 芯片，在由 1500 例非小细胞肺癌病例和 1500 例匹配对照（均为白种人）组成的测试组中识别影响肺癌风险的新遗传变异。目标 2：在另外 1000 个病例和 1000 个对照的复制集中，使用 GoldenGate 测定，我们将评估从 Aim1 中确定的前 1500 个 SNP，以满足 P<0.1 标准，或者通过结合已发表结果的合理优先顺序方法进行选择、SNP 类型、进化生物学、理化特性和单倍型标记 SNP。目标 3：通过与目标 2 中相同的方法选择的 50 个 SNP 的侧翼区域进行精细定位，将先验信息与计算机方法相结合以预测功能。对于这 50 个 SNP 中的每一个，我们将在每个基因区域平均选择 10 个额外的 SNP，以在所有 2500 个病例和 2500 个对照中进行重新基因分型。目标 4. 通过整合已建立的流行病学风险因素和基因变异数据来扩展我们的流行病学风险预测模型。我们将应用机器学习工具来识别基因-环境和基因-基因相互作用。协变量包括既往肺气肿、哮喘、花粉热、灰尘和石棉暴露、吸烟特征、癌症家族史和抗炎药物的使用。国际肺癌联盟将在即将制定的提案中进行外部验证。我们在一项大型、有力的研究中全面评估候选途径中变异的方法将适用于炎症发挥重要病因作用的各种其他癌症部位，以及具有强烈炎症成分的非肿瘤疾病，例如气肿。有用的肺癌风险预测模式对公共卫生的潜力是巨大的。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls.

DOI：
10.1007/s00439-013-1270-y
发表时间：
2013-05
期刊：
HUMAN GENETICS
影响因子：
5.3
作者：
Brenner, Darren R.;Brennan, Paul;Boffetta, Paolo;Amos, Christopher I.;Spitz, Margaret R.;Chen, Chu;Goodman, Gary;Heinrich, Joachim;Bickeboeller, Heike;Rosenberger, Albert;Risch, Angela;Muley, Thomas;McLaughlin, John R.;Benhamou, Simone;Bouchardy, Christine;Lewinger, Juan Pablo;Witte, John S.;Chen, Gary;Bull, Shelley;Hung, Rayjean J.
通讯作者：
Hung, Rayjean J.

Mathematical modeling of auxin transport in protoxylem and protophloem of Arabidopsis thaliana root tips.

拟南芥根尖原木质部和原韧皮部生长素运输的数学模型。

DOI：
10.1142/s0219720013400106
发表时间：
2013
期刊：
Journal of bioinformatics and computational biology
影响因子：
1
作者：
Novoselova,EkaterinaS;Mironova,VictoriaV;Omelyanchuk,NadyaA;Kazantsev,FedorV;Likhoshvai,VitalyA
通讯作者：
Likhoshvai,VitalyA

Derived SNP alleles are used more frequently than ancestral alleles as risk-associated variants in common human diseases.