Pharmacogenetic Determinants of Outcomes Following Cance

癌症后结果的药物遗传学决定因素

• 批准号: 6755583
• 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/6755583
• 关键词: breast neoplasms; cancer complication; cancer risk; chemical carcinogenesis; chemical structure function; clinical research; disease /disorder etiology; drug adverse effect; drug related neoplasm /cancer; estrogen inhibitor; estrogens; gene environment interaction; genetic polymorphism; genetic screening; genetic susceptibility; hormone regulation /control mechanism; human subject; insulinlike growth factor; neoplasm /cancer chemotherapy; neoplasm /cancer epidemiology; neoplasm /cancer genetics; outcomes research; patient care planning; stimulant /agonist; tamoxifen; uterus neoplasms

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 pharmacogenetics project is now well underway. We have begun 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. The first phase of this project is targeting the women who participated in NSABP's Tamoxifen Breast Cancer Prevention Trial ("P1"), with invasive breast cancer the first outcome to be investigated. A "case-only" study design has been chosen. This proposal is now undergoing IRB review at NSABP. We have been granted access to DNA specimens that were previously extracted and anonymized for another study. The development of the assays for the 30 polymorphisms selected for study is complete, and they are now being validated using CEPH families. Genotyping will begin as soon as IRB approval has been obtained. Subsequent phases of this project may include: (a) analysis of the non-invasive breast cancers which developed in P1 subjects; (b) analysis of the endometrial neoplasms from this same study; and (c) genotyping of a random sample of the entire P1 cohort, to permit seeking evidence of a major effect for candidate genes, and to obtain the absolute risk estimates required (if evidence of a gene-tamoxifen interaction is found) to apply these findings clinically. (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 Core Genotyping Facility 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 (PLCO)screening trial. The first analysis will target PLCO participants who were found to have either colorectal cancer or advanced adenomatous polyps at the time of their baseline colonscopy. IGF1/IGF-BP3 levels are also being studied among participants in the Honolulu Heart Cohort who developed prostate cancer during prospective follow-up. (c) The next major pharmacogenetic study now under development will target treatment-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Genes involved in the activation and detoxification of specific chemotherapeutic agents, as well as DNA repair genes, will be evaluated as modifiers of the risk of MDS/AML in this setting. Case material will be drawn from the data bases maintained by the national cooperative clinical trial groups. NSABP is the first group to join this project; others are expected to follow. This project has been developed by Dr. Charles Rabkin, during his sabbatical year with CGB. (d) 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 among women with breast cancer participating in clinical trials, the option of extending our studies of tamoxifen/gene interactions relative to the endometrial neoplasms which developed in P1 trial participants, and the possibility of studying genetic determinants of bleomycin-related pulmonary fibrosis among men treated for testicular cancer. (e) CGB staff have provided cancer genetics consultation to the Food and Drug Administration in support of its investigation of a cluster of malignant lymphomas which has been identified among patients exposed to a novel class of therapeutic agents, the tumor necrosis factor inhibitors. These medications have been approved recently for the treatment of refractory rheumatoid arthritis and for severe Crohn's disease. Thirty-nine persons with lymphoma have been identified by MedWatch, FDA's post-market adverse event surveillance system. A manuscript is now in press describing the findings of the initial investigation. Available data do not permit drawing a firm conclusion regarding the etiologic relationship between exposure to these medications and the subsequent development of lymphoma, but there is sufficient cause for concern to warrant additional analytic epidemiologic study in an effort to resolve this important question. (f) An excess of Ewing's sarcoma as a second primary malignancy following retinoblastoma has been reported by a CGB staff member. An excess risk of Merkel cell carcinoma, a rare cutaneous neuroendocrine malignancy, was observed in patients who were immunologically compromised as a result of infection with HIV.

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 的第一个药物遗传学项目目前正在顺利进行。我们已经开始研究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。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。该项目的第一阶段针对的是参加 NSABP 的他莫昔芬乳腺癌预防试验（“P1”）的女性，其中浸润性乳腺癌是第一个要调查的结果。选择了“仅案例”研究设计。该提案目前正在 NSABP 接受 IRB 审查。我们已获准访问之前为另一项研究而提取并匿名化的 DNA 样本。选定用于研究的 30 种多态性的检测方法开发已完成，目前正在使用 CEPH 家族对其进行验证。一旦获得 IRB 批准，基因分型就会开始。该项目的后续阶段可能包括： (a) 分析 P1 受试者中发生的非浸润性乳腺癌； (b) 对同一研究中的子宫内膜肿瘤进行分析； (c) 对整个 P1 队列的随机样本进行基因分型，以允许寻找候选基因主要影响的证据，并获得将这些发现应用于临床所需的绝对风险估计（如果发现基因-他莫昔芬相互作用的证据）。 (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。与核心基因分型设施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（PLCO）筛查试验参与者肿瘤风险的决定因素进行研究。第一项分析将针对在基线结肠镜检查时发现患有结直肠癌或晚期腺瘤性息肉的 PLCO 参与者。 IGF1/IGF-BP3 水平也在檀香山心脏队列的参与者中进行研究，这些参与者在前瞻性随访期间患上前列腺癌。 (c) 目前正在开发的下一个主要药物遗传学研究将针对与治疗相关的骨髓增生异常综合征（MDS）和急性髓系白血病（AML）。参与特定化疗药物的激活和解毒的基因以及 DNA 修复基因将被评估为这种情况下 MDS/AML 风险的修饰因素。案例材料将从国家合作临床试验组维护的数据库中提取。 NSABP是第一个加入该项目的小组；预计其他国家也会效仿。该项目由 Charles Rabkin 博士在 CGB 休假期间开发。 (d) 预计将寻求和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试验参与者中前瞻性收集种系 DNA。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风险的影响，选择扩展我们对P1试验参与者中发生的子宫内膜肿瘤的他莫昔芬/基因相互作用的研究，以及研究接受睾丸癌治疗的男性中博来霉素相关肺纤维化的遗传决定因素的可能性。 (e) CGB 工作人员向食品和药物管理局提供了癌症遗传学咨询，以支持其对一组恶性淋巴瘤的调查，这些恶性淋巴瘤是在接触新型治疗剂（肿瘤坏死因子抑制剂）的患者中发现的。这些药物最近已被批准用于治疗难治性类风湿性关节炎和严重克罗恩病。 FDA 的上市后不良事件监测系统 MedWatch 已识别出 39 名淋巴瘤患者。一份描述初步调查结果的手稿现已出版。现有数据无法就接触这些药物与随后发生淋巴瘤之间的病因关系得出明确的结论，但有足够的理由值得关注，需要进行额外的分析流行病学研究，以努力解决这一重要问题。 (f) 一名 CGB 工作人员报告称，尤文氏肉瘤是继视网膜母细胞瘤之后的第二原发恶性肿瘤。在因感染艾滋病毒而免疫功能受损的患者中观察到患默克尔细胞癌（一种罕见的皮肤神经内分泌恶性肿瘤）的风险过高。