Pharmacogenetic Studies of Acute Myeloid Leukemia

描述（由申请人提供）： 许多学术机构和合作组织保存了大量的肿瘤组织档案，这些组织来自具有匹配治疗和临床结果信息的患者。这些档案已被用于特定肿瘤的分子表征，以及旨在研究获得性遗传改变对临床结果测量的影响的预后研究。在药物遗传学研究中利用这些肿瘤档案的兴趣越来越大，这些研究涉及评估体质遗传多态性与治疗相关毒性和预后之间的关联。很少有人关注在药物遗传学研究中使用患病组织作为基因组DNA来源的适当性。我们认为，在利用储存的肿瘤组织作为基因组DNA来源的药物遗传学研究中，重要的第一步应该是证明在患病组织和配对的非患病组织中测量的多态性之间的一致性。由于我们的长期兴趣在于对急性髓性白血病进行药物遗传学研究，因此我们建议在我们的主要具体目标中系统地研究使用存档的骨髓样本的效用，以研究一组基因的预后意义，这些基因参与AML化疗的药效学，在一组特征明确的AML患者中。在我们的第二个具体目标中，我们建议利用从该方法学研究中产生的数据，对AML患者中与AML治疗相关的这组多态性在毒性和临床结局指标中的作用进行初步研究。具体来说，我们将比较来自Roswell Park癌症研究所的100名AML患者的配对骨髓和颊细胞之间的遗传多态性数据。在本研究的初步研究中，我们将评估编码参与AML治疗中使用的化疗药物代谢的蛋白质的遗传多态性的作用，对化疗药物产生的氧化损伤的保护，以及AML患者临床结局指标中的耐药性。本研究生成的数据将通过以下方式指导AML大规模药物遗传学研究的设计：a）提供关于使用现有骨髓组织库的适当性的数据，和B）通过提供关于骨髓组织中基因型数据潜在错误分类的数据以及关于遗传多态性对临床结局影响的初步数据，直接考虑样本量。

DESCRIPTION (provided by applicant): Many academic institutions and Cooperative Groups maintain extensive archives of tumor tissue from patients with matching treatment and clinical outcome information. Such archives have been utilized for molecular characterizations of specific tumors, as well as prognostic studies aimed at investigating the effect of acquired genetic alterations on clinical outcome measures. There is increasing interest in utilizing these tumor archives in pharmacogenetic studies, which are concerned with assessing the associations between constitutional genetic polymorphisms and treatment-related toxicity and prognosis. Little effort has focused on the appropriateness of using diseased tissue as a source of genomic DNA in pharmacogenetic studies. We believe that an important first step in pharmacogenetic studies that utilize stored tumor tissue as a source of genomic DNA should be to demonstrate concordance between polymorphism measured in diseased and paired non-diseased tissue. Since our long-term interest lies in conducting a pharmacogenetic investigation of acute myeloid leukemia, we propose in our primary specific aim to systematically investigate the utility of using archived bone marrow samples for an investigation on the prognostic significance of a panel of genes involved in the pharmacodynamics of AML chemotherapy in a well-characterized group of AML patients. In our secondary specific aim, we propose to utilize the data generated from this methodological investigation for a pilot study on the role of this panel of polymorphisms relevant to AML treatment in toxicity and clinical outcome measures among AML patients. Specifically, we will compare genetic polymorphism data between paired bone marrow and buccal cells from 100 AML patients from Roswell Park Cancer Institute. In the pilot study component of this research we will assess role of genetic polymorphisms encoding for proteins involved in metabolism of chemotherapeutic agents used in the treatment of AML, protection from oxidative damage generated by chemotherapeutic agents, and drug resistance in clinical outcome measures among AML patients. Data generated from this research will guide the design of large-scale pharmacogenetic studies of AML by a) providing data on the appropriateness of using existing bone marrow tissue banks, and b) direct sample size considerations by providing data on potential misclassification of genotype data in bone marrow tissue, as well as preliminary data on the effect of genetic polymorphisms on clinical outcomes.