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分为三种类型：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很重要的。为了达到这个目的，基础科学家已经在实验系统中发现了多种基因，这些基因可能在这些癌症的病因学中很重要。与此同时，流行病学家已经确定了与癌症风险增加有关的环境因素（例如，吸烟和肺癌）。此外，统计遗传学家已经表明，对于大量恶性肿瘤，癌症发展和存活的风险在整个人群中并不是均匀分布的。考虑到癌症表型的复杂性和癌细胞基因组结构的巨大破坏，对晚期疾病的新治疗方法的近期成功持谨慎乐观的态度是合理的。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记，以区分患乳腺癌的高风险人群，或因预防干预而出现并发症的高风险人群。为了实现这些目标，研究人员使用了两个样本人群：一个是来自他莫昔芬大型3期试验（13388名妇女）的病例收集，另一个是病例对照研究（总共750名妇女）。实验室的初步研究使用了一组不同的病例对照人群（总共493人），重点关注候选乳腺癌易感基因，包括那些参与雌激素生物合成和代谢的基因。芳香化酶基因（Cyp19）的等位基因分布在病例和对照组之间存在显著差异。此外，该实验室还开发了MALDI-TOF质谱分析，用于分析雌激素生物合成和代谢途径的广泛基因标记，特别关注文献中描述的功能显著的等位基因变异。目前正在对38种变异进行评估，其中仅针对他莫昔芬的研究，以解决预防干预带来的并发症的潜在关联，并在病例对照人群中确定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肺癌发病风险的基因。在这项研究中，我们评估了参与I期和II期代谢的14个基因中的15个变异。当在756个吸烟者样本中评估这15个候选易感基因变异，并将结果引入逻辑回归模型（根据遗传背景进行调整）时，只有GSTA4与肺癌显著相关。还确定了烟草烟雾、膳食摄入量和候选基因变异之间的相互作用。在对329名吸烟者的分层分析中，在GSTM1无效个体中，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。利用G1/S检查点通路进行了解释肺癌基因表达的路径分析方法的试点应用。选择这一途径是因为它已被证明在肺癌的发展中起着重要作用。最初的研究考察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.