BIOMARKERS OF TREATMENT RELATED LEUKEMIA

治疗相关白血病的生物标志物

• 批准号: 6701287
• 负责人: Carolyn A Felix
• 金额: $ 36.94万
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701287
• 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：（根据调查员的摘要进行了改编） 工作是开发新的途径来识别正在进行的抗癌疗法 有白血病作为治疗并发症的风险增加，并促进 在疾病过程中早期检测白血病克隆。为了 转移性神经母细胞瘤的儿童接受N6治疗，发生率 白血病为7％。约40％的病例与烷基化剂疗法有关， 染色体5和/或7损失；大约40％的MLL基因的易位 在与DNA有关的白血病中发生的染色体带11q23 拓扑异构酶II抑制剂。由于其针对神经母细胞瘤的功效N6 治疗将纳入高危神经母细胞瘤试验中 儿童癌症组。 N6中使用的依托泊苷，阿霉素和环磷酰胺 通过细胞色素P-450（CYP）3A代谢治疗；所有与 白血病是一种治疗并发症。代谢物具有遗传毒性特性 这可能与白血病有关。 CYP3A4基因的启动子是 多态性。先前的研究表明，CYP3A4野生型基因型增加 和CYP3A4变体基因型降低了与治疗相关白血病的风险 与MLL基因易位。先前的研究还表明MLL基因 可以在课程疗法的早期出现易位。 DNA拓扑异构酶II抑制剂的剂量。 MLL提出了一个极端的例子 涉及许多伴侣基因的易位； Southern印迹分析和cDNA Panhandle PCR是两种可以跟踪易位易位的方法 样品不管伴侣基因如何。他们假设CYP3A4基因型 MLL基因易位是与治疗相关的相关生物标志物 白血病。合作小组使用N6治疗的计划不仅要求 系统的调查是谁最有风险的人，但也提供了独特的调查 临床机会检查CYP3A4基因型和MLL基因易位 在治疗试验的背景下，相关的生物标记物。目的 AIM 1是验证CYP3A4基因型与治疗相关的关联 白血病。目标2和3的目的是确定和比较效用 通过Southern印迹分析和cDNA检测的MLL基因易位 Panhandle PCR，作为白血病特异性标记，可预测 疾病。目标4的目的是探索MLL基因的基线频率 未经治疗的儿科患者的易位，被诊断为神经母细胞瘤和 确定化学疗法在过程中如何影响该频率 治疗。与治疗相关的白血病的危险因素知之甚少。 预测生物标志物测定将使主要修改主要修改 癌症疗法并为早期干预提供新的机会。