Molecular Epidemiology of Smoking & Breast Cancer

描述(申请人提供)：尽管进行了大量研究，但吸烟和乳腺癌之间的关系仍然存在争议。卡罗莱纳乳腺癌研究(CBCS)和原位癌研究(CIS)是对北卡罗来纳州浸润性乳腺癌和原位癌进行的基于人群的病例对照研究。一半的受试者是白人，一半是非裔美国人。在CBCS中，我们最近发现吸烟影响乳腺癌中P53突变的患病率和谱。最值得注意的是，与从不吸烟的人相比，现在吸烟者携带P53突变的可能性是不吸烟者的两倍(OR=2.11；95%CI=1.17-3.78)，易位(OR=3.37；95%CI=1.03-11.0)的可能性是吸烟者的3倍以上，T：A易位(OR=10.53；95%CI=1.77-62.5)的可能性是不吸烟者的10倍以上。病例对照分析支持我们的病例-病例研究，并表明当前吸烟(OR=7.30；95%C_1=1.38-38.5)和长时间(&gt；20年)吸烟(OR=8.65；95%C_1=1.60-46.8)与携带G：C-和T：A易位的乳腺癌风险显著相关。这些和其他结果清楚地表明，吸烟的遗传毒性效应在吸烟者的乳腺肿瘤中表现为P53突变指纹，并表明吸烟与乳腺癌的发生有关。在这项拟议的研究中，我们将评估来自CBCS和CIS研究的800个浸润性和200个原位乳腺肿瘤在一系列在肺癌和早期乳腺癌中经常缺失的染色体位点上的杂合性缺失。此外，先前发现在吸烟者的肺肿瘤中有几个基因座发生了优先缺失；这些基因座包括FHIT(3p14.2)、3p21.3、9p21、8p21-23和P53(17p13)。其他在乳腺癌中发生杂合性缺失但与吸烟没有特殊关系的基因座也将被评估，包括17q21(BRCA1)、13q12(BRCA2)和16q22.1(E-钙粘素)。参与致癌物代谢或DNA修复的基因的遗传变异可能会影响对烟草致癌物的易感性，从而在肿瘤中形成体细胞变化。我们将首先比较吸烟者和非吸烟者中整体和个别基因位点杂合性缺失的发生率，以及杂合性缺失与乳腺肿瘤中p53突变的发生之间的关系。作为一个更具探索性的目标，我们将确定GST和NAT代谢酶或DNA修复酶(XRCC1、APE、HOGG1、XPA、XPD、XPF等)的常见种系变异是否会改变与吸烟相关的LOH或P53突变的患病率。由体细胞遗传改变(如LOH或P53突变)定义的乳腺癌亚群的特征，加上对生殖系多态和吸烟暴露的分析，应该为评估吸烟对乳腺癌的影响提供一个全面的方法。如果乳腺癌可以部分归因于吸烟，那么预防吸烟或戒烟应该减少接触，从而降低乳腺癌的发病率。

DESCRIPTION (provided by applicant): Despite considerable research, the relationship between cigarette smoking and breast cancer remains controversial. The Carolina Breast Cancer Study (CBCS) and the Carcinoma In Situ (CIS) Study are population-based, case-control studies of invasive breast cancer and carcinoma in situ in North Carolina. Half of the subjects are white and half are African American. In the CBCS, we have recently found that cigarette smoking influences both the prevalence and spectrum of p53 mutations in breast tumors. Most notably, current smokers were twice as likely to harbor p53 mutations (OR=2.11; 95% C1=1.17-3.78), over 3 times as likely to harbor transversions (OR=3.37; 95% C1=1.03-11.0) and over 10 times as likely to harbor G:C--)T:A transversions (OR=10.53; 95% CI= 1.77-62.5) compared to never smokers. Case-control analyses support our case-case studies, and indicate that current smoking (OR=7.30; 95% C1=1.38-38.5) and long (>20 year) duration of smoking (OR=8.65; 95% C1=1.60-46.8) are significantly associated with increased risk of breast cancers carrying G:C->T:A transversions. These and other results clearly demonstrate that the genotoxic effect of smoking is manifested as a p53 mutational fingerprint in the breast tumors of smokers, and implicate smoking in breast cancer development. In the proposed study, we will evaluate 800 invasive and 200 in situ breast tumors from the CBCS and CIS studies for LOH at a series of chromosomal loci that are frequently deleted in both lung cancer and early forms of breast cancer. Furthermore, several of these loci were previously found to undergo preferential deletion in the lung tumors of smokers; these loci include FHIT (3p14.2), 3p21.3, 9p21, 8p21-23 and p53 (17p13). Additional loci that undergo LOH in breast cancer, but which have no specific relationship with smoking will also be evaluated, including 17q21 (BRCA1), 13q12 (BRCA2), and 16q22.1 (E-cadherin). Genetic variation in genes involved in carcinogen metabolism or DNA repair may influence susceptibility to tobacco smoke carcinogens, and thus the formation of somatic alterations in tumors. We will first compare the prevalence of LOH, both overall and at individual loci, in smokers and nonsmokers, and the relationship between LOH and the occurrence of p53 mutations in breast tumors. As a more exploratory aim, we will then determine whether common germline variants of the GST and NAT metabolizing enzymes, or of DNA repair enzymes (XRCC1, APE, HOGG1, XPA, XPD, XPF, and others), modify the prevalence of LOH or p53 mutations associated with smoking. The characterization of subsets of breast cancer defined by somatic genetic alterations such as LOH or p53 mutation, together with analysis of germline polymorphisms and tobacco smoke exposure should provide a comprehensive approach for evaluating the effects of smoking in breast cancer. If breast cancer can be attributed, in part, to cigarette smoking, then smoking prevention or cessation should reduce exposure and thus decrease the incidence of breast cancer.