Genetics of Tobacco and Alcohol Related Cancers

描述（由申请人提供）：尽管肺癌和上气消化道（UADT）癌症主要由烟草和酒精引起，但只有少数重度吸烟者和重度饮酒者会患上肺癌或UADT癌症。一种可能的解释是，由于遗传因素，致癌产物的代谢、内剂量水平以及随后的DNA修复和细胞周期控制机制在个体之间差异很大。该项目的长期目标是在两项独立的研究中调查45个基因的作用，这些基因可能与肺癌和UADT癌症的易感性有关。第一项是对中欧肺癌和UADT癌症的研究，涉及约2300例肺癌病例、1200例UADT癌症病例和2800例对照。第二项是在南美洲进行的一项单独的UADT癌症研究，涉及约2100例病例和1700例对照。这两项研究都是按照相同的方案进行的，包括收集生活方式和职业史的高质量详细信息，以及收集血液以提取DNA。45个基因的108个snp的基因分型将使用自动化和预先验证的DNA微阵列进行。这些基因包括参与烟草制品、酒精和其他潜在致癌物代谢的基因（如CYPs、GSTs、ADH2、ADH3、MPO），以及参与DNA修复的基因（如XRCC1、XRCC3、XPD、XPF）、肿瘤抑制（p53、p16、CCND1）和尼古丁成瘾（多巴胺D2和D4受体基因）。使用这些大样本量，我们将准确地测量每个基因在肺癌和UADT癌中的总体影响。随后，将测量基因组合的影响（基因-基因相互作用），以及通过酒精和烟草消费和职业史确定的特定亚组中单个基因的影响（基因-环境相互作用）。统计技术将包括单倍型重建，经验贝叶斯和半贝叶斯分析，以控制假阳性结果，以及复杂途径的建模。

DESCRIPTION (provided by applicant): Even though lung and upper aero-digestive tract (UADT) cancers are predominantly caused by tobacco and alcohol, only a minority of heavy smokers and heavy drinkers will develop lung or UADT cancer. A possible explanation for this is that the metabolisation of carcinogenic products, the level of internal dose and subsequent DNA repair and cell cycle control mechanisms vary widely between individuals because of genetic factors. The broad long-term goal of this project will be to investigate in two separate studies the role of 45 genes which are potentially involved in the susceptibility of lung and UADT cancers. The first is a study of lung and UADT cancers in Central Europe, involving approximately 2300 lung cancer cases, 1200 UADT cancer cases and 2800 controls. The second is a separate study of UADT cancer in South America involving approximately 2100 cases and 1700 controls. Both studies are conducted to an identical protocol involving the collection of high quality detailed information on lifestyle and occupational history, as well as blood collection for DNA extraction. Genotyping of 108 SNPs for the 45 genes will be conducted using automated and pre-validated DNA microarrays. The genes comprise those involved in the metabolism of tobacco products, alcohol and other potential carcinogens (e.g. CYPs, GSTs, ADH2, ADH3, MPO), as well as genes involved in DNA repair (e.g. XRCC1, XRCC3, XPD, XPF), tumour suppression (p53, p16, CCND1 ) and nicotine addiction (dopamine D2 and D4 receptor genes). Using these large sample sizes, we will accurately measure the overall effect of each gene in lung and UADT cancer. Subsequently, the effect of combinations of genes will be measured (gene-gene interaction), as well as the effect of individual genes in specific subgroups identified by alcohol and tobacco consumption and occupational history (gene-environment interaction). Statistical techniques will include haplotype reconstruction, empirical Bayes and semi-Bayes analysis to control for false positive results, and modeling of complex pathways.