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率。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，或预防干预的并发症风险个体。两个样本人群被用于实现这些目标：一个是来自他莫昔芬大型3期试验（13，388名女性）的病例收集，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（Cyp 19）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个变异正在评估的情况下，只有他莫昔芬研究，以解决潜在的关联与并发症的预防干预，并在病例对照人群中，以确定标志物的指示乳腺癌的发展风险高。该实验室还试图通过检查候选基因变异，在病例对照研究中，以确定基因，修改发展肺癌的风险。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GSTA 4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的作用，在肺癌risk.Pilot应用路径分析方法来解释肺癌基因表达已进行利用G1/S检查点途径。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。

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 are being 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 are being 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.