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 在研究为控制初始癌症而对患者进行的治疗与随后发生第二种癌症的风险之间的关系方面有着悠久而杰出的历史。这代表了一种独特的观察情况，可以研究人类暴露于明确的化学致癌物和电离辐射的后果。现在有机会将这些研究转移到基因领域，通过研究影响化学致癌物生物利用度的基因常见多态性与临床感兴趣的各种结果之间的关系。此类研究可以识别出第二类癌症、血栓事件、急性骨髓抑制、治疗反应甚至生存风险特别高的人群亚组。还存在识别遗传变异的潜力，这可以降低不良后果的风险。此类信息可能会对临床决策产生重大影响。 (a) CGB 进军这一领域的首次尝试目前正在顺利进行：我们计划对与他莫昔芬和雌激素生物利用度相关的基因的遗传多态性以及由于接触他莫昔芬而患子宫内膜癌和乳腺癌的风险进行研究。临床试验表明，接触他莫昔芬的女性患子宫内膜癌的风险增加，而患乳腺癌的风险降低。一般来说，这些差异归因于他莫昔芬是作为雌激素激动剂还是雌激素拮抗剂发挥作用的组织特异性差异。我们假设影响他莫昔芬和/或雌激素代谢的基因的遗传变异可能会识别出或多或少可能从他莫昔芬给药中受益的女性亚组。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女性的 DNA 样本进行。这项研究的正式提案将在未来几个月内提交给 DCEG 的高级顾问小组和 NSABP 的科学顾问委员会。 (b) 关于外显率较低的基因中的常见变异作为癌症风险修饰因子这一主题的另一个变化是我们正在进行的对作为 IGF1 信号通路一部分的基因的遗传多态性的研究。 IGF1（一种具有促有丝分裂和抗细胞凋亡作用的细胞因子）水平升高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。与人口遗传学实验室和流行病学与生物统计学项目主任办公室合作，正在系统地鉴定这些基因的遗传变异，然后将其作为前列腺癌、肺癌、结肠癌和卵巢癌筛查参与者中肿瘤风险的决定因素进行研究(c) 预计将寻求并确定对常见遗传变异与各种癌症治疗相关结果的风险之间的关系进行其他分析的机会。特别有希望的是与各个国家临床试验合作小组合作的机会，既探索使用存档的肿瘤样本作为基因研究 DNA 来源的可能性，也考虑从选定的临床参与者中前瞻性收集种系 DNA试验。正在考虑的想法包括评估遗传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风险的影响，以及将我们对他莫昔芬和子宫内膜癌的研究扩展到其他历史临床试验队列的选择。