GENETIC POLYMORPHISMS AS DETERMINANTS OF OUTCOMES FOLLOW

DCEG在研究患者控制初始癌症的治疗与随后发展为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。这是一种独特的观察情况，在这种情况下，人们可以研究人类暴露于明确界定的化学致癌物和电离辐射的后果。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各种临床结果之间的关系，现在有机会将这些研究转移到遗传领域。这些研究可以确定具有第二种癌症、血栓形成事件、急性骨髓抑制、治疗反应甚至生存风险的人群亚群。识别基因变异也有可能降低不良后果的风险。此类信息可能对临床决策产生重大影响。(a) CGB在这一领域的首次尝试目前正在顺利进行：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。临床试验表明，接触他莫昔芬的妇女患子宫内膜癌的风险增加，患乳腺癌的风险降低。一般来说，这些差异归因于他莫昔芬作为雌激素激动剂还是雌激素拮抗剂的组织特异性差异。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确定哪些妇女亚组或多或少可能从他莫昔芬的施用中受益。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的高级咨询小组和NSABP的科学咨询委员会。(b)关于低渗透基因内常见变异作为癌症风险修饰因子的另一个变化是我们正在进行的基因遗传多态性研究，这些基因是IGF1信号通路的一部分。IGF1是一种具有有丝分裂和抗凋亡作用的细胞因子，其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。在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的合作下，正在系统地确定这些基因的遗传变异，然后在前列腺癌、肺癌、结肠癌和卵巢癌筛查试验的参与者中作为肿瘤风险的决定因素进行研究。(c)预期将寻求和确定机会，对共同遗传变异与各种癌症治疗有关的结果的危险之间的关系进行其他分析。特别有希望的是与各种国家临床试验合作小组合作的机会，既可以探索使用存档肿瘤样本作为基因研究DNA来源的可能性，也可以考虑在选定的临床试验中从参与者那里收集生殖系DNA。正在考虑的想法包括评估基因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。

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.