Pharmacogenomic factors associated with severe acute toxicities and survival in pediatric Latino patients with acute lymphoblastic leukemia

1个项目摘要/摘要 研究项目2：拉美裔儿童患急性淋巴细胞白血病(ALL)的风险最高 3累积复发率高，生存率低。我们假设所有的拉丁裔儿童 4将表现出更严重的急性毒性和独特的药物毒性集群模式。我们还认为，这些 毒性和聚集性在拉丁裔患者中更普遍，与药物基因组因素有关，并 6与复发风险增加和无事件生存率降低有关。为了证明这些观点，我们 7将验证先前与聚乙二醇胺相关的毒性簇的工作，然后应用这种方法来描述毒性 在所有治疗过程中使用的其他药物的8个集群。我们将定义严重急性呼吸综合征与 9种毒物和毒物簇对复发和无事件生存风险的影响并检查药物基因组学 使用候选和全基因组关联研究的毒性和集群的10。最后，我们将描述 11通过分析其他药物基因组数据集，从我们的队列中发现变异风险等位基因的频率。 12候选人计划和目标：伯恩哈特博士渴望成为一名领先的、独立的、临床科学家，在 13临床药物基因组学。她的首要目标是通过翻译来改善对癌症儿童的护理 14基因组科学对床边临床决策的影响。这一目标将通过发展 15在临床药物基因组学方面的知识和研究专长。伯恩哈特博士将参加正式和 16与她的研究有关的非正式培训，包括药物基因组学的教学和实践经验， 17翻译生物学和流行病学。她将由Michael Scheurer博士和Richard Gibbs博士指导， 18位分子流行病学和人类遗传学领域的知名研究人员(尊敬的)。伯恩哈特博士的建议 19委员会将在正式会议和一对一互动期间指导她的研究和职业发展。 贝勒医学院(BCM)对伯恩哈特博士的职业发展进行了投资，确保75% 21本申请书中所述的受保护时间，以及对她长期成功的承诺。 22环境：职业发展和研究活动将在BCM和德克萨斯儿童学校进行 23医院(TCH)。BCM是一所一流的医学院和学术健康科学中心，在资金方面排名很高 24来自美国国立卫生研究院和美国国家科学基金会。BCM积极培训3000多名员工 25名医学、研究生和卫生专业的学生和研究员。德克萨斯州儿童癌症和血液学 26中心是BCM/TCH的联合项目，是美国最大的儿科癌症和血液学项目。 27个研究和培训机会将出现在TXCH流行病学计划，BCM人类基因组 28个测序中心和TCH分子病理学项目。BCM和TCH的课程提供广泛的 29个接受指导和自我指导的培训、授课课程、同伴互动和持续培训的机会 30跨多个科学领域的专业发展。

1 PROJECT SUMMARY/ABSTRACT 2 Research Project: Latino children have the highest risk of developing acute lymphoblastic leukemia (ALL), a 3 higher cumulative incidence of relapse, and lower survival rates. We hypothesize that Latino children with ALL 4 will exhibit more severe acute toxicities and a unique pattern of drug toxicity clusters. We also believe that these 5 toxicities and clusters are more prevalent in Latino patients, are related to pharmacogenomic factors and are 6 associated with an increased risk of relapse and reduced event-free survival. To demonstrate these points, we 7 will validate prior work with pegaspargase-related toxicity clusters, then apply this approach to describe toxicity 8 clusters for other agents used throughout ALL treatment. We will define the relationship between severe acute 9 toxicities and toxicity clusters on the risk of relapse and event-free survival and examine the pharmacogenomics 10 of toxicities and clusters using candidate and genome-wide association studies. Lastly, we will describe the 11 frequency of variant risk alleles from our cohorts by analyzing other pharmacogenomic datasets. 12 Candidate plan and goals: Dr. Bernhardt aspires to be a leading, independent, clinician-scientist in the field of 13 clinical pharmacogenomics. Her overarching goal is to improve the care of children with cancer by translating 14 genomic science to clinical decision-making at the bedside. This goal will be accomplished by developing 15 knowledge and research expertise in clinical pharmacogenomics. Dr. Bernhardt will participate in formal and 16 informal training relevant to her research, including didactic and hands-on experiences in pharmacogenomics, 17 translational biology, and epidemiology. She will be mentored by Drs. Michael Scheurer and Richard Gibbs, 18 renowned investigators in molecular epidemiology and human genetics (respectfully). Dr. Bernhardt’s advisory 19 committee will guide her research and career development during formal meetings and one-on-one interactions. 20 Baylor College of Medicine (BCM) has invested in Dr. Bernhardt’s career development by assuring 75% 21 protected time as described in this application, and commitment to her success in the long-term. 22 The Environment: Career development and research activities will be conducted at BCM and Texas Children's 23 Hospital (TCH). BCM is a premiere medical school and academic health science center, highly ranked in funding 24 from the National Institutes of Health and the National Science Foundation. BCM actively trains more than 3,000 25 medical, graduate, and health professions students and fellows. Texas Children’s Cancer and Hematology 26 Centers, a joint BCM/TCH program, is the largest pediatric cancer and hematology program in the United States. 27 Research and training opportunities will occur within the TXCH Epidemiology Program, BCM Human Genome 28 Sequencing Center, and TCH Molecular Pathology programs. Programs at BCM and TCH offer extensive 29 opportunities for mentored and self-directed training, didactic coursework, peer interactions, and ongoing 30 professional development across multiple scientific domains.