Molecular Genetic Epidemiology of leading U.S. Cancers

美国主要癌症的分子遗传学流行病学

• 批准号: 6433305
• 负责人: Kenneth H Buetow
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433305
• 关键词: biochemical evolution; breast neoplasms; family genetics; gene environment interaction; gene expression; genetic susceptibility; human genetic material tag; human population genetics; lung neoplasms; molecular genetics; neoplasm /cancer epidemiology; neoplasm /cancer genetics; prostate neoplasms

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).

1999年，美国成年人的新癌症诊断中几乎有三种类型：肺癌，乳腺癌和前列腺癌。 如果在降低总癌症发生率方面要取得重大进展，那么找到预防这些主要肿瘤的方法将很重要。 为此，基础科学家已经确定了在实验系统中可能在这些癌症的病因中很重要的各种基因。 一致的是，流行病学家已经确定了与癌症风险增加（例如吸烟和肺癌）相关的环境因素。 此外，统计遗传学家表明，对于大量的恶性肿瘤，发展和存活的癌症的风险并不统一分布在整个人群中。 但是，迄今为止，很难综合这些不同研究的结果。很少有调查足够全面，可以纳入这两个环境风险因素并检查它们之间的相互作用。 因此，该项目的目的确定了个体遗传变异在改变环境因素施加的癌症风险中的作用。 此类研究的最终目标是鉴定具有遗传确定癌症敏感性的个体。为了进行这些研究，我们正在进行基于医院的病例对照研究。 目的是获得上述每个癌症部位的1000例和1000个控件的集合。迄今为止，该研究累积了500多个乳腺癌病例，350例前列腺癌病例，600例肺癌病例和700例对照样品。 该研究是在扩展的排毒基因集合中鉴定出新的基于DNA的变化，这些变化可能介导外源性和内源性暴露的致癌作用。 一旦确定，与吸烟者和非吸烟者的性别匹配对照相比，在候选基因座的变异相关性的测试。 将评估关联取决于案例特征。使用从每种案例获得的家族史信息和控制参考个体，将评估家庭中癌症聚集的模式。 最后，将确定家庭内部的聚集与候选基因及其家人中候选基因的变化之间的关系。迄今为止，使用标准核酸基于标准的基于核酸的分析，已经在肺癌子集中研究了GSTA1，GSTA4，GSTM1，GSTM1，GSTM1，GSTM2，GSTM3，GSTP1，GSTP1，GSTT2，GSTT2，MGST，EPHX1和NQO1。检查了每个基因座的一个或多个基于DNA的变体。 先前在文献中描述了所使用的变体，或者是通过使用NCI CGAP遗传注释计划的SNP管道的数据挖掘获得的数据挖掘来获得的。为了说明人口分层的可能性，使用PE-BIOSYSYSS AMPFLSTR PROFILER PLUS法医面板进行了基因分型，该面板为10个高杂合性STR基因座。 这种基于Muliplex荧光的测定法可以使用小于0.25 ng的总DNA来表征所有10个基因座。 这些标记用于调整与疾病/控制状态无关的背景遗传差异的比较，这可能会混淆。 调整程序利用进化遗传学和流行病学的统计方法。 在调整种群分层之前，四个基因座的变体在病例子集中显示出显着关联（<0.05），并具有吸烟史的对照：GSTA4，GSTM3，GSTM3，GSTT1和GSTT2。 调整遗传背景差异后，所有四个基因座都保留了显着性：GSTA4 OR = 1.33（1.01-1.77），GSTM3 OR = 1.47（1.03-2.08），GSTT1或= 2.15（1.31-3.52）和GSTT2或GSTT2或= 1.32 OR = 1.32（1.01-1.01-1.72）。