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。鉴于癌症表型的复杂性和癌细胞基因组构成的急剧破坏，对晚期疾病的新治疗方法的近期成功仅持谨慎乐观态度是合理的。更有效的短期策略可能是早期诊断或预防。对于大多数癌症类型，在疾病的早期阶段进行治疗干预已显示出很高的疗效。 该实验室正试图确定遗传体质标志物，以区分患有乳腺癌的高风险个体，或预防干预措施的并发症风险个体。将使用两个样本人群来实现这些目标：一个是从他莫昔芬的大型III期试验（13，388名女性）中收集的病例，另一个是病例对照研究（共750名）。在实验室中使用不同的病例对照人群集（共493个）进行的初步研究集中在候选乳腺癌易感基因上，包括参与雌激素生物合成和代谢的基因。芳香化酶基因（Cyp19）的等位基因分布的显着差异，观察病例和对照之间。此外，该实验室还开发了MALDI-TOF MS分析，用于解剖雌激素生物合成和代谢途径的基因标记物的扩展集合，特别关注文献中描述的功能显著的等位基因变体。38种变异将在仅他莫昔芬研究的病例中进行评估，以解决与预防干预并发症的潜在关联，并在病例对照人群中进行评估，以确定指示乳腺癌发展高风险的标志物。 该实验室还试图通过在病例对照研究中检查候选基因变异来确定改变患肺癌风险的基因。在这项研究中，评估了参与I期和II期代谢的14个基因中的15个变体。当在756个吸烟者样本子集中评估这15个候选易感基因变体，并将结果引入逻辑回归模型（在遗传背景调整后）时，只有GSTA4与肺癌显著相关。研究了烟草烟雾、膳食摄入和候选基因变异之间的相互作用。在对329名吸烟者进行分层分析时，健康的饮食模式（高纤维和碳水化合物摄入量，低蛋白质和动物脂肪摄入量）与GSTM 1缺失个体肺癌风险降低相关。这一结果表明，饮食因素可以影响致癌物代谢酶在肺癌风险中的作用。 已利用G1/S检查点途径进行了解释肺癌基因表达的路径分析方法学的试点应用。选择这一途径是因为它已被证明在肺癌的发展中起重要作用。最初的研究检查了基因之间相关性的拟合模型是否反映了当前关于肺肿瘤中这一途径发生变化的生物学知识。对17个正常肺细胞系和55个肺癌细胞系的基因表达数据进行通径分析。对该通路中的许多关键基因，包括TGF-β、SMAD4、p53、gsk3b、cdc25A、p27、p21、cdk2、细胞周期蛋白E、cdk6、cdk4、细胞周期蛋白D和Rb，已经有了很多了解，并且基于现有数据对模型进行了测试。第一个也是最简单的模型研究了上游基因对Rb表达的直接影响。在正常细胞中，35%的Rb表达的变化似乎与cdks和cyclins的表达有关。这些蛋白质的增加，信号G1到S的过渡，对应于Rb表达的减少。肿瘤样本显示较低的Rb表达，Rb表达并没有强烈的影响cdk4和cdk6。细胞周期蛋白E对Rb表达的影响似乎在肿瘤中增加，但细胞周期蛋白E及其调节因子cdk2存在明显的解耦，表明这些作用可能受到不良调节。这一初步研究与文献中关于这些基因在正常细胞和癌细胞中的研究是一致的，并表明，路径分析可以用来可靠地检验假设的变化模式的相关性发生在正常和疾病状态。

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. Given the complexity of cancer phenotypes and the dramatic disruption of cancer cells' genomic constitution, it is rational to only be cautiously optimistic about the near term success of novel therapeutic approaches to end-stage disease. A more efficacious short-term strategy may be early diagnosis or prevention. For most cancer types, therapeutic intervention in early stages of disease has demonstrated high rates of efficacy. The laboratory is attempting to identify genetic constitutional markers that distinguish individuals at high risk for developing breast cancer, or at risk of developing complications from prevention interventions. Two sample populations will be used to achieve these goals: a case only collection from a large phase 3 trial of Tamoxifen (13,388 women) and a case-control study (750 in all). Preliminary studies in the laboratory using a distinct case-control population set (493 in all) have focused on candidate breast cancer susceptibility genes, including those involved in estrogen biosynthesis and metabolism. A significant difference in allelic distribution of the aromatase gene (Cyp19) was observed between cases and controls. In addition, the laboratory has developed MALDI-TOF MS assays on an extended collection of gene markers useful in dissecting estrogen biosynthetic and metabolic pathways, focusing specifically on functionally significant allelic variants described in the literature. Thirty-eight variants will be assessed in the case only Tamoxifen studies to address potential associations with complications from prevention intervention, and in the case-control population to identify markers indicative of high risk for breast cancer development. The laboratory is also attempting to identify genes that modify the risk of developing lung cancer by examining candidate gene variation in a case-control study. In this study, fifteen variants in fourteen genes involved in Phase I and Phase II metabolism were evaluated. When these 15 candidate susceptibility gene variants were assessed in a 756-sample subset of smokers, and the results introduced into logistic regression models (following adjustments for genetic background), only GSTA4 was significantly associated with lung cancer. The interaction among tobacco smoke, dietary intake and candidate gene variation was also determined. On stratified analysis of 329 smokers, a healthy dietary pattern (high intakes of fibers and carbohydrates and low intakes of protein and animal fat) was associated with decreased lung cancer risk among GSTM1 null individuals. This result suggests that dietary factors can influence carcinogen metabolizing enzymes effects in lung cancer risk. Pilot application of path analysis methodologies for interpreting lung cancer gene expression has been performed utilizing the G1/S checkpoint pathway. This pathway was chosen because it has been shown to play an important role in the development of lung cancer. The initial study examined whether the fitted models of correlation between genes reflect current biological knowledge about the changes that occur in this pathway in lung tumors. Gene expression data from 17 normal lung and 55 lung carcinoma cell lines was used for path analysis. Much is known about many of the key genes in the pathway, which includes TGF-b, SMAD4, p53, gsk3b, cdc25A, p27, p21, cdk2, cyclin E, cdk6 cdk4, cyclin D and Rb, and models were tested based on the available data. The first and simplest model examined the direct influence of upstream genes on Rb expression. In normal cells, 35% of the variation in Rb expression appeared related to the expression of cdks and cyclins. Increases in these proteins, which signal G1 to S transition, corresponded to decreases in Rb expression. Tumor samples showed lower Rb expression, and Rb expression was not strongly influenced by cdk4 and cdk6. The influence of cyclin E over Rb expression appeared to increase in tumors, but there was an apparent decoupling of cyclin E and its regulator cdk2 suggesting that these effects may be poorly regulated. This initial study is consistent with the literature concerning these genes in normal and cancer cells, and suggests that path analysis can be used to reliably test hypotheses concerning changes in the patterns of correlations occurring in the normal and disease state.