Drug Metabolism, DNA Repair & Second Cancers

描述（由申请人提供）： 候选人：弗里德曼博士是一名儿科肿瘤学家，对癌症流行病学，预防和长期健康相关的治疗结果感兴趣。 工作环境：弗雷德哈钦森癌症研究中心（FHCRC），华盛顿大学（UW）和儿童医院和区域医疗中心（CHRMC）组成了西雅图癌症护理联盟（SCCA），促进了研究资源的共享。 这项研究将在约翰·波特博士的指导下在FHCRC癌症预防研究计划中进行。 研究计划：有待检验的假设是，化疗药物代谢、DNA合成所需核苷酸供应和DNA修复的遗传差异改变了SMN发生的风险。 为了解决这一假设，我们将在两个明确定义的SMN高风险队列中检查参与这些过程的基因的等位基因变体。 这些是接受常规治疗的儿童癌症患者，以及接受造血干细胞移植治疗的患者。 选择用于研究的基因包括亚甲基四氢叶酸还原酶（MTHFR）、谷胱甘肽-S-转移酶（GST）、GSTT 1、GSTM 1、GSTM 3、GSTP 1、细胞色素P-450（CYP）CYP 2C 9、CYP 2C 19、CYP 3A 4、硫嘌呤甲基转移酶、甲基鸟嘌呤DNA甲基转移酶、ERCC 1、XPD、XRCC 1、XRCC 2、XRCC 3、XRCC 4和XRCC 5。 将在每个队列中使用巢式病例对照方法，以检查特定等位基因变异与SMN发生的相关性。 职业规划与发展：弗里德曼博士的职业目标是成为一名专注于癌症控制，预防和长期治疗结果的转化研究人员。 该奖项将提供分子生物学，癌症遗传学，流行病学和生物统计学方面的持续指导培训。 弗里德曼博士将在弗雷德哈钦森癌症研究中心的公共卫生科学部和华盛顿大学的公共卫生学院接受教育。 本研究结果可应用于癌症幸存者的第二恶性肿瘤和其他不良长期健康相关结果的预防策略的制定。

DESCRIPTION (provided by applicant): Candidate: Dr. Friedman is a pediatric oncologist with research training and interest in cancer epidemiology, prevention and long-term health-related outcomes of therapy. Environment: The Fred Hutchinson Cancer Research Center (FHCRC), University of Washington (UW) and Children's Hospital and Regional Medical Center (CHRMC) comprise the Seattle Cancer Care Alliance (SCCA), which facilitates sharing of research resources. This research will be performed in the FHCRC Cancer Prevention Research Program under the mentorship of Dr. John Potter. Research Plan: The hypothesis to be tested is that genetic differences in the metabolism of chemotherapeutic agents, in the provision of nucleotides for DNA synthesis, and in DNA repair modify risk of SMN development. To address this hypothesis, we will examine allelic variants of genes involved in these processes in two well-defined cohorts at high risk of SMN. These are patients treated for childhood cancer with conventional therapy, and patients treated with hematopoietic stem cell transplant. The genes chosen for study include methylenetetrahydrofolate reductase (MTHFR), Glutathione-S-transferase (GST), GSTT1, GSTM1, GSTM3, GSTP1, Cytochrome P-450 (CYP) CYP2C9, CYP2C19, CYP3A4, thiopurine methyltransferase, methylguanine DNA methyltransferase, ERCC1, XPD, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC5. Nested case-control methodology will be used, in each of the cohorts, to examine the association of specific allelic variants with SMN development. Career Plan and Development: Dr. Friedman's career goal is to be a translational researcher with a focus on cancer control, prevention, and long-term outcomes of therapy. This award will provide continued mentored training in molecular biology, cancer genetics and epidemiology and biostatistics. Educational opportunities will be provided to Dr. Friedman in the Division of Public Health Sciences at Fred Hutchinson Cancer Research center and in the School of Public Health at the University of Washington. The findings of this research can be applied to the development of preventive strategies of second malignant neoplasms and other adverse long-term health-related outcomes for cancer survivors.