Molecular Genetic Epidemiology of leading U.S. Cancers

在美国，几乎一半的成年人新诊断的癌症将属于三种类型：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很重要。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，吸烟与肺癌）。此外，统计遗传学家已经表明，对于大量的恶性肿瘤，发展和存活癌症的风险在整个人群中并不是均匀分布的。然而，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，既纳入环境风险因素，并审查它们之间的相互作用。因此，本项目的目的是确定个体遗传变异在改变环境因素引起的癌症风险中所起的作用。这些研究的最终目标将是确定具有遗传决定的癌症易感性的个体。 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1000例上述癌症部位的病例和1000例对照。这项研究正在确定一个扩展的解毒基因集合中新的基于DNA的变异，这些基因可能介导外源性和内源性暴露的致癌作用。一旦确定，将进行与吸烟者和非吸烟者性别匹配对照相比的候选基因座变异相关性检验。将根据病例特征进行相关性评估。使用从每个病例和对照参考个体获得的家族史信息，将评估家族中癌症聚集的模式。最后，将确定先证者及其家族成员中的候选基因变异与家族内聚集之间的关系。 GSTA 1、GSTA 4、GSTM 1、GSTM 2、GSTM 3、GSTP 1、GSTT 1、GSTT 2、mGST、EPHX 1和NQO 1已经在肺癌亚组中检查了先前在文献中描述的基于DNA的变体，或者通过利用NCI的CGAP遗传注释倡议的SNP管道的数据挖掘公开可获得的序列数据而获得。为了解释群体分层的可能性，使用PE-Biosystems AmpFlSTR Profiler Plus法医面板的10个高杂合性STR基因座对群体进行基因分型。这些标记物用于调整与疾病/控制状态无关的背景遗传差异的比较，这些差异可能混淆结果。在调整人群分层之前，在有吸烟史的病例和对照组中，四个基因座的变异显示出显著的相关性（p <0.05）：GSTA 4、GSTM 3、GSTT 1和GSTT 2，并且在调整遗传背景差异后，所有四个基因座都保持了显著性。在仅限于吸烟者的亚组分析中，并针对遗传背景进行了调整，观察到GSTA 4与肺癌显著相关（p = 0.022）。在非吸烟者中，（调整遗传背景）观察到GSTT 1和GSTT 2与肺癌显著相关，p值分别为0.0341和0.0285。 为探讨遗传易感性和饮食在肺癌风险中可能的联合作用，进一步分析了438名有饮食信息的受试者。聚类分析使用四种主要饮食成分（蛋白质，碳水化合物，动物脂肪和膳食纤维）的营养密度进行，以确定具有相似饮食模式的人群。对329名吸烟者进行分层分析，健康的饮食模式与GSTM 1基因敲除者肺癌风险降低显著相关，OR=0.46（0.21-1.01）。健康饮食和基因型的保护作用中观察到的个体谁不携带GSTP 1的纯合性OR=0.16（0.05-0.58），当与那些纯合和有一个不健康的饮食。这些数据表明，饮食因素可以影响某些编码代谢酶的基因在肺癌风险中的作用。在没有阐明饮食成分之间复杂的相关性的情况下，使用饮食模式进行调整可能有助于阐明致癌物代谢基因多态性的真正影响。

Almost half of new cancer diagnoses in adults in the U.S. 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 to 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. The study is identifying new DNA-based variation in an extended collection of detoxification genes which may mediate the carcinogenic effects of exogenous 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. GSTA1, GSTA4, GSTM1, GSTM2, GSTM3, GSTP1, GSTT1, GSTT2, mGST, EPHX1, and NQO1 have been examined in the lung cancer subset for DNA-based variants previously described in the literature, or obtained through data mining publicly available sequence data utilizing the SNPpipeline 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. These markers were used to adjust the comparisons for background genetic differences unrelated to disease/control status that could confound outcomes. Prior to adjustment for population stratification, variants at four loci showed significant associations (p <0.05) within the subset of cases and controls with a history of smoking: GSTA4, GSTM3, GSTT1, and GSTT2, and all four loci retained significance following adjustment for genetic background differences. In a subset analysis restricted to smokers, and adjusted for genetic background, GSTA4 was observed to be significantly associated with lung cancer (p = 0.022). Among nonsmokers, (adjusted for genetic background) GSTT1 and GSTT2 were observed to be significantly associated with lung cancer with p values of 0.0341 and 0.0285, respectively. To investigate possible joint effects of genetic susceptibility and diet in lung cancer risk, 438 subjects with dietary information were further analyzed. Cluster analysis was performed using nutrient densities of the four major dietary constituents (protein, carbohydrate, animal fat, and dietary fiber) to identify groups of persons with similar dietary patterns. On stratified analysis of 329 smokers, a healthy dietary pattern was significantly associated with a decrease lung cancer risk among GSTM1 null individuals OR=0.46 (0.21-1.01). A protective effect of healthy diet and genotype was observed among individuals who do not carry the homozygosity of GSTP1 OR=0.16 (0.05-0.58), when compared to those who were homozygous and had an unhealthy diet. These data suggest that dietary factors can influence the role of certain genes encoding metabolic enzymes in lung cancer risk. Without clarification of the complex correlations between dietary constituents, adjustments using dietary patterns may be useful to elucidating genuine effects of polymorphisms in genes responsible for carcinogen metabolism.