Molecular Genetic Epidemiology of leading U.S. Cancers

1999年，美国成年人新诊断的癌症中，几乎有一半是三种类型：肺癌、乳腺癌和前列腺癌。如果要在降低癌症总发病率方面取得重大进展，找到预防这些主要肿瘤的方法将是重要的。为此，基础科学家已经在实验系统中确定了各种基因，这些基因可能在这些癌症的病因学中起着重要作用。一致地，流行病学家已经确定了与癌症风险增加相关的环境因素(例如吸烟和肺癌)。此外，统计遗传学家已经表明，对于大量的恶性肿瘤，患上癌症并存活下来的风险并不均匀地分布在整个人群中。然而，到目前为止，很难综合这些不同研究的结果。很少有调查足够全面，既能纳入环境风险因素，又能检查它们之间的相互作用。因此，本项目的目标是确定个体基因变异在改变环境因素造成的癌症风险方面所起的作用。这类研究的最终目标将是确定具有基因决定的癌症易感性的个人。为了进行这些研究，我们正在进行一项以医院为基础的病例对照研究。目标是获得上述每个癌症部位的1000个病例和1000个对照的集合。到目前为止，这项研究已经积累了500多例乳腺癌病例、350例前列腺癌病例、600例肺癌病例和700例对照样本。这项研究正在确定一系列解毒基因中新的基于DNA的变异，这些基因可能介导了外源性和内源性暴露的致癌效应。一旦确定，将进行候选基因变异与吸烟者和非吸烟者的性别匹配对照病例的相关性测试。将根据案例特征对关联性进行评估。利用从每个病例和对照参考个体获得的家族史信息，将评估癌症在家庭中聚集的模式。最后，将确定家系内聚集与先证者及其家庭成员候选基因变异之间的关系。到目前为止，GSTA1、GSTA4、GSTM1、GSTM2、GSTM3、GSTP1、GSTT1、GSTT2、MGST、EPHX1和NQO1已经用标准的基于核酸的分析方法在肺癌亚群中进行了检测。对每个基因座检测一个或多个基于DNA的变异。所使用的变体或者是先前在文献中描述的，或者是通过利用NCI的CGAP遗传注释倡议的SNP管道对公开可用的序列数据进行数据挖掘而获得的。为了解释群体分层的可能性，使用PE-BiosSystems AmpFlSTR Profiler Plus法医小组的10个高杂合度STR基因座对群体进行了基因分型。这种基于多重荧光的分析方法允许使用不到0.25 ng的总DNA来表征所有10个基因座。这些标记被用来调整背景基因差异的比较，这些差异与疾病/控制状况无关，可能会混淆结果。调整程序利用了进化遗传学和流行病学的统计方法。在对人群分层进行调整之前，在病例和对照的子集内，四个基因座的变异与吸烟史有显著的相关性(a&lt；0.05)：GSTA4、GSTM3、GSTT1和GSTT2。在对遗传背景差异进行校正后，4个座位均保持显著差异：GSTA4的OR=1.33(1.01-1.77)，GSTM3的OR=1.47(1.03-2.08)，GSTT1的OR=2.15(1.31-3.52)，GSTT2的OR=1.32(1.01-1.72)。

Almost half of new cancer diagnoses in adults in the U.S. in 1999 will be of three types: cancers of the lung, breast, and prostate. If significant progress is to be made in reducing total cancer incidence, it will be important to finds means of preventing these major tumors. Toward this end, basic scientists have identified a variety of genes in experimental systems that may be important in the etiology of these cancers. Concordantly, epidemiologists have identified environmental factors that are associated with increased cancer risk (e.g., smoking and lung cancer). In addition, statistical geneticists have shown that for a large number of malignancies, the risk of developing and surviving cancer is not uniformly distributed throughout the population. However, to date, it has been difficult to synthesize the results of these diverse studies. Few investigations have been comprehensive enough to incorporate both environmental risk factors and to examine the interactions among them. Thus, it is the objective of this project determine the role individual genetic variation plays in modifying the risk of cancer imposed by environmental factors. The ultimate goal of such studies will be the identification of individuals with genetically determined cancer susceptibility. To perform these studies, we are conducting a hospital-based case-control study. The goal is to obtain 1000 cases of each of the above cancer sites and a collection of 1000 controls. To date the study has accrued more than 500 breast cancer cases, 350 prostate cancer cases, 600 lung cancer cases, and 700 control samples. The study is identifying new DNA-based variation in an extended collection of detoxification genes which may mediate the carcinogenic effects of exogeneous and endogenous exposures. Once identified, tests for association of variation in candidate loci in cases when compared to sex-matched controls who are smokers and non-smokers will be conducted. Assessment of association dependent on case characteristics will be made. Using family history information obtained from each case and control reference individual, the patterns of cancer aggregation in families will be assessed. Finally, the relationship between aggregation within families and variation of candidate genes in the probands and their family members will be determined. To date, GSTA1, GSTA4, GSTM1, GSTM2, GSTM3, GSTP1, GSTT1, GSTT2, mGST, EPHX1, and NQO1 have been examined in the lung cancer subset using standard nucleic acid- based assays. Each locus was examined for one or more DNA-based variant. Variants used were either previously described in the literature, or obtained through data mining publicly available sequence data utilizing the SNP pipeline of the NCI's CGAP Genetic Annotation Initiative. To account for the possibility of population stratification, the population was genotyped using the PE-Biosystems AmpFlSTR Profiler Plus forensic panel of 10 high heterozygosity STR loci. This muliplex fluorescence-based assay permits all 10 loci to be characterized using less than 0.25 ng total DNA. These markers were used to adjust the comparisons for background genetic differences unrelated to disease/control status that could confound outcomes. Adjustment procedures utilized statistical methods from evolutionary genetics and epidemiology. Prior to adjustment for population stratification, variants at four loci showed significant associations (a<0.05) within the subset of cases and controls with a history of smoking: GSTA4, GSTM3, GSTT1, and GSTT2. All four loci retained significance following adjustment for genetic background differences: GSTA4 OR= 1.33 (1.01- 1.77), GSTM3 OR= 1.47 (1.03 - 2.08), GSTT1 OR=2.15 (1.31 - 3.52), and GSTT2 OR= 1.32 (1.01 - 1.72).