Use of Stored Bone Marrow Samples for Pharmacogenetic S*

描述(由申请人提供)： 许多学术机构和合作组织保存着大量来自患者的肿瘤组织档案，提供匹配的治疗和临床结果信息。这些档案已被用于特定肿瘤的分子特征，以及旨在调查获得性基因改变对临床结果衡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越来越有兴趣，这些研究涉及评估体质基因多态性与治疗相关毒性和预后之间的关系。很少有人关注在药物遗传学研究中使用病变组织作为基因组DNA来源的适当性。我们认为，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的重要第一步应该是证明在疾病组织和配对的非疾病组织中测量的多态之间的一致性。由于我们的长期兴趣在于对急性髓系白血病进行药物遗传学研究，我们建议在我们的主要具体目标中，系统地研究利用存档的骨髓样本在一组特征良好的AML患者中调查一组参与AML化疗药效学的基因的预后意义。在我们的第二个特定目标中，我们建议利用从这一方法学调查中产生的数据进行一项初步研究，以了解与AML治疗相关的这组基因多态性在AML患者的毒性和临床结果衡量中的作用。具体地说，我们将比较来自罗斯威尔公园癌症研究所的100名AML患者的配对骨髓和口腔细胞之间的遗传多态数据。在这项研究的试点研究部分，我们将评估编码参与治疗AML的化疗药物代谢的蛋白质的基因多态在AML患者中的作用，保护其免受化疗药物产生的氧化损伤，以及在临床结果评估中的耐药性。这项研究产生的数据将通过a)提供关于使用现有骨髓组织库的适当性的数据，以及b)通过提供关于骨髓组织中可能的基因数据错误分类的数据，以及关于基因多态对临床结果的影响的初步数据，来指导AML的大规模药物遗传学研究的设计。

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.