GENETIC POLYMORPHISMS AS DETERMINANTS OF OUTCOMES FOLLOW

遗传多态性作为结果的决定因素如下

• 批准号: 6435286
• 负责人: MARK H GREENE
• 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/6435286
• 关键词: breast neoplasms; cancer risk; clinical research; family genetics; genetic polymorphism; genetic susceptibility; human population genetics; human subject; neoplasm /cancer genetics; neoplasm /cancer therapy; outcomes research; ovary neoplasms; tamoxifen

DCEG has a long and distinguished history of investigating the relationship between treatments administered to patients to control an initial cancer, and the risk of subsequently developing a second cancer. This represents a unique observational situation in which one can study the consequences of human exposure to well defined chemical carcinogens and to ionizing radiation. The opportunity now exists to move these studies into the genetic arena, by investigating the relationship between common polymorphisms in genes affecting the bioavailability of chemical carcinogens and various outcomes of clinical interest. Such studies could identify population sub-groups which are at particular risk of second cancers, thrombotic events, acute myelosuppression, response to treatment or even survival. The potential also exists to identify genetic variants which may reduce the risk of adverse outcomes. Information of this kind could have a significant impact on clinical decision-making. (a) CGB's first foray into this arena is now well underway: we are planning a study of genetic polymorphisms in the genes related to tamoxifen and estrogen bioavailability and the risk of developing endometrial cancer and breast cancer as a result of exposure to tamoxifen. Clinical trials have demonstrated that women exposed to tamoxifen are at increased risk of developing endometrial cancer and at decreased risk of developing breast cancer. In general terms, these differences have been attributed to tissue specific variations in whether tamoxifen acts as an estrogen agonist or an estrogen antagonist. We hypothesize that genetic variations in the genes which affect tamoxifen and/or estrogen metabolism may identify sub-groups of women who are more or less likely to benefit from the administration of tamoxifen. It is hoped that this study will be conducted using banked DNA specimens from women who participated in NSABP's Tamoxifen Breast Cancer Prevention Trial. A formal proposal for this study will be brought both to DCEG's Senior Advisory Group and NSABP's Scientific Advisory Board within the next several months. (b) Another variation on the theme of common variants within less penetrant genes as modifiers of cancer risk is our ongoing study of genetic polymorphisms in genes which are part of the IGF1 signaling pathway. Elevated levels of IGF1, a cytokine with both mitogenic and anti-apoptotic effects, have been associated with increased risks of a variety of different cancers, including premenopausal breast, colon, prostate and lung cancer. In collaboration with the Laboratory of Population Genetics and the Office of the Director, Epidemiology & Biostatistics Program, genetic variations in these genes are being systematically identified and then studied as determinants of neoplasm risk among participants of the Prostate, Lung, Colon and Ovarian Cancer screening trial.(c) It is anticipated that opportunities for other analyses of the relationship between common genetic variants and the risk of various cancer treatment-related outcomes will be sought and identified. Particularly promising is the opportunity of working with various national clinical trials cooperative groups, both to explore the possibilities of using archived tumor samples as a source of DNA for gene study, as well as to consider the prospective collection of germline DNA from participants in selected clinical trials. Among the ideas under consideration are an evaluation of genetic influences upon the risk of developing contralateral breast cancer and acute leukemia among women with breast cancer participating in clinical trials, and the option of extending our studies of tamoxifen and endometrial cancer into other historical clinical trials cohorts.

DCEG具有研究对患者控制初始癌症的治疗之间的关系的悠久而杰出的历史，以及随后患第二种癌症的风险。这代表了一种独特的观察状况，在这种情况下，人们可以研究人类暴露于定义明确的化学致癌物和电离辐射的后果。现在，通过研究影响化学致癌物生物利用度的基因中的共同多态性和各种临床兴趣结果的基因中的共同多态性之间的关系，现在存在将这些研究转移到遗传领域的机会。这样的研究可以鉴定有第二种癌症，血栓性事件，急性骨髓抑制，对治疗或什至生存期的人群亚组。潜力也存在于鉴定遗传变异，从而降低不良结果的风险。这种信息可能会对临床决策产生重大影响。 （a）CGB的首次进军现在正在进行中：我们正在计划研究与他莫昔芬和雌激素生物利用度有关的基因中的遗传多态性，以及由于暴露于他莫昔芬而导致子宫内膜癌和子宫内膜癌和乳腺癌的风险。临床试验表明，暴露于他莫昔芬的妇女患子宫内膜癌的风险增加，并且患乳腺癌的风险降低。一般而言，这些差异归因于组织特异性变化，他莫昔芬是雌激素激动剂还是雌激素拮抗剂。我们假设影响他莫昔芬和/或雌激素代谢的基因中的遗传变异可能会发现或多或少受益于他莫昔芬的女性的亚组。希望这项研究将使用参加NSABP的他莫昔芬乳腺癌预防试验的妇女的银行DNA标本进行。这项研究的正式建议将在未来几个月内将DCEG的高级咨询小组和NSABP的科学咨询委员会提出。 （b）在较少的渗透基因中，作为癌症风险的修饰者，常见变体主题的另一种变化是我们正在对IGF1信号通路的一部分基因的遗传多态性的持续研究。 IGF1水平升高（一种具有有丝分裂和抗凋亡作用的细胞因子，与多种不同癌症的风险增加有关，包括绝经前乳腺癌，结肠癌，前列腺癌和肺癌。通过与人口遗传学实验室和流行病学与生物统计学计划的主任办公室合作，这些基因的遗传变异被系统地识别出来，然后研究为前列腺参与者的肿瘤风险的决定因素，肺，结肠癌和卵巢癌筛查试验的风险和遗传性的风险。结果将被寻求和确定。特别有希望的是有机会与各种国家临床试验合作小组合作，既可以探索使用存档的肿瘤样品作为基因研究的DNA来源的可能性，又要考虑从某些临床试验中参与者的前瞻性收集种系DNA。在考虑的思想中，评估遗传影响对参与临床试验的乳腺癌女性患对侧乳腺癌和急性白血病的风险，以及将我们对他莫昔芬和子宫内膜癌研究扩展到其他历史临床试验的研究。