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的第一个药物遗传学项目现在正在进行中。我们已经开始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，以及由于他莫昔芬的暴露而患上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。该项目的第一阶段是针对参加NSABP的他莫昔芬乳腺癌预防试验（“ P1”）的妇女，其中侵入性乳腺癌的第一个结果要研究。选择了“仅大案”研究设计。该提案现已在NSABP进行IRB审查。我们已获得访问以前提取并匿名进行另一项研究的DNA标本的访问权限。选择进行研究的30种多态性的测定法的开发已经完成，现在使用CEPH家族对其进行验证。一旦获得IRB批准，基因分型将开始。该项目的随后阶段可能包括：（a）分析在P1受试者中开发的非侵入性乳腺癌； （b）对这项研究的子宫内膜肿瘤的分析； （c）对整个P1队列的随机样本进行基因分型，以允许寻求候选基因产生主要影响的证据，并获得所需的绝对风险估计（如果发现基因 - 莫昔芬相互作用的证据）在临床上应用这些发现。 （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。与核心基因分型设施和流行病学与生物统计学计划主任办公室合作，这些基因的遗传变异被系统地鉴定出来，然后研究为前列腺，肺，结肠癌和卵巢癌（PLCO）筛查试验的参与者中肿瘤风险的决定因素。第一个分析将针对PLCO参与者，他们在基线共剖分时被发现患有大肠癌或晚期腺瘤息肉。在前瞻性随访期间患上前列腺癌的参与者中，还研究了IGF1/IGF-BP3水平。 （c）现在正在开发的下一项主要的药物遗传学研究将靶向与治疗相关的骨髓增生综合征（MDS）和急性髓样白血病（AML）。在这种情况下，将评估参与特定化学治疗剂的激活和解毒以及DNA修复基因的基因以及DNA修复基因。案例材料将从国家合作临床试验小组维护的数据库中得出。 NSABP是第一个加入该项目的组。预计其他人将遵循。该项目是由查尔斯·拉布金（Charles Rabkin）博士在CGB的休假期间开发的。 （d）预计将寻求和识别出常见遗传变异与各种与癌症治疗相关结果的风险之间关系的其他分析的机会。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。 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的工作人员向食品药物管理局提供了癌症遗传学咨询，以支持其研究一组恶性淋巴瘤，这些淋巴瘤已被鉴定出暴露于新型治疗剂的患者中，即肿瘤坏死因子抑制剂。这些药物最近已被批准用于治疗难治性类风湿关节炎和严重的克罗恩病。 FDA的后市场不良事件监视系统MedWatch已经确定了39人患有淋巴瘤的人。现在在媒体上描述了一份手稿，描述了初始研究的发现。可用的数据不允许对这些药物接触与随后的淋巴瘤发展之间的病因关系得出确定的结论，但是有足够的原因值得保证其他分析流行病学研究，以解决这一重要问题。 （f）CGB工作人员报告了视网膜母细胞瘤之后的尤因肉瘤作为第二个主要恶性肿瘤。默克尔细胞癌的过量风险是一种罕见的皮肤神经内分泌恶性肿瘤，在因HIV感染而受到免疫学损害的患者中观察到。