BIOMARKERS OF TREATMENT RELATED LEUKEMIA

治疗相关白血病的生物标志物

• 批准号: 6085918
• 负责人: Carolyn A Felix
• 金额: $ 32.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6085918
• 关键词: DNA gyrase; alkylating agents; biomarker; chromosome translocation; clinical research; cyclophosphamide; cytochrome P450; doxorubicin; enzyme inhibitors; etoposide; genetic markers; human subject; iatrogenic disease; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neuroblastoma; pediatric neoplasm /cancer; polymerase chain reaction; southern blotting

DESCRIPTION: (Adapted from the investigator's abstract) The objective of this work is to develop new avenues to identify undergoing anticancer therapy who are at increased risk of leukemia as a treatment complication and to facilitate detection of the leukemic clone earlier in the course of the disease. For children with metastatic neuroblastoma receiving N6 therapy, the incidence of leukemia is 7%. About 40% of cases are related to alkylating agent therapy and have chromosome 5 and/or 7 loss; about 40% have translocation of the MLL gene at chromosome band 11q23, which occurs in leukemias related to DNA topoisomerase II inhibitors. Because of its efficacy against neuroblastoma, N6 therapy will be incorporated into the high-risk neuroblastoma trial for the Children's Cancer Group. Etoposide, doxorubicin and cyclophosphamide used in N6 therapy are metabolized by cytochrome P-450 (CYP) 3A; all are associated with leukemia as a treatment complication. The metabolites have genotoxic properties that may be relevant to leukemogenesis. The promoter of the CYP3A4 gene is polymorphic. Prior studies showed that the CYP3A4 wild-type genotype increased and CYP3A4 variant genotypes decrease the risk of treatment-related leukemia with MLL gene translocations. Prior studies also showed that the MLL gene translocation can be present early in the course therapy at how cumulative doses of DNA topoisomerase II inhibitors. MLL presents an extreme example of a translocation involving many partner genes; Southern blot analysis and cDNA panhandle PCR are two methods that can track the translocations in preleukemic samples regardless of the partner gene. They hypothesize that CYP3A4 genotype and MLL gene translocations are relevant biomarkers for treatment-related leukemia. The plans of the cooperative group to use N6 therapy not only mandate systematic investigation of who is most at risk, but also provide a unique clinical opportunity to examine CYP3A4 genotype and MLL gene translocations as a relevant biomarkders in the context of the therapeutic trial. The purpose of aim 1 is to validate the association of CYP3A4 genotype with treatment-related leukemia. The purpose of aims 2 and 3 is to determine and compare the utility of MLL gene translocations, detected by Southern blot analysis and cDNA panhandle PCR, as leukemia-specific markers that predict development of disease. The purpose of aim 4 is to explore the baseline frequency of MLL gene translocations in untreated pediatric patients diagnosed with neuroblastoma and to determine how chemotherapy affects this frequency during the course of treatment. Risk factors for treatment-related leukemia are poorly understood. Predictive biomarker assays will enable rational modifications of primary cancer therapies and provide new opportunities for early intervention.

描述：(改编自调查人员的摘要)这项研究的目的 工作是开发新的途径来识别正在接受抗癌治疗的人 作为一种治疗并发症，白血病的风险增加，并有助于 在病程的早期检测白血病克隆。为 接受N6治疗的儿童转移性神经母细胞瘤的发生率 白血病的发病率为7%。约40%的病例与烷化剂治疗有关， 有5号和/或7号染色体丢失；约40%有MLL基因易位 在染色体11q23，出现在与DNA相关的白血病 拓扑异构酶II抑制剂。由于其对神经母细胞瘤的疗效，N6 治疗将纳入高危神经母细胞瘤试验 儿童癌症组织。足叶乙苷、阿霉素和环磷酰胺在N6中的应用 治疗由细胞色素P-450(CYP)3A代谢；所有这些都与 白血病是一种治疗并发症。这些代谢物具有遗传毒性。 这可能与白血病的发生有关。CYP3A4基因的启动子是 多态的。先前的研究表明，CYP3A4野生型基因增加 CYP3A4基因变异可降低治疗相关白血病的风险 有MLL基因易位。先前的研究也表明MLL基因 易位可以在疗程治疗的早期出现在如何累积 DNA拓扑异构酶II抑制剂的剂量。MLL提供了一个极端的例子， 涉及多个配对基因的易位；Southern杂交分析和cDNAs 狭长柄聚合酶链式反应是两种可以追踪白血病前期易位的方法 样本，而不考虑伴侣的基因。他们推测，细胞色素P3A4基因 MLL基因易位是治疗相关的相关生物标志物 白血病。合作小组使用N6疗法的计划不仅要求 对谁是最危险的人进行系统调查，但也提供了一个独特的 检测细胞色素P3A4基因和MLL基因易位的临床机会 治疗试验背景下的相关生物标记物。目的 目的1是验证CYP3A4基因与治疗相关的相关性 白血病。目标2和目标3的目的是确定和比较效用 用Southern印迹分析和cDNA检测MLL基因易位 狭长柄聚合酶链式反应作为预测白血病发生的特异性标记物 疾病。目的4的目的是探索MLL基因的基线频率 未经治疗的神经母细胞瘤和神经母细胞瘤儿童患者的易位 为了确定化疗在治疗过程中如何影响这一频率 治疗。与治疗相关的白血病的风险因素知之甚少。 预测性生物标志物分析将使原始数据的合理修改成为可能 癌症治疗，并为早期干预提供了新的机会。