Radiation Sensitivity, DNA Repair and Second Cancers

辐射敏感性、DNA 修复和第二种癌症

• 批准号: 7123897
• 负责人: Debra L Friedman
• 金额: $ 26.2万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123897
• 关键词: DNA repair; blood /lymphatic neoplasm; cancer risk; clinical research; drug metabolism; drug related neoplasm /cancer; environment related neoplasm /cancer; genetic susceptibility; hematopoietic tissue transplantation; human subject; neoplasm /cancer epidemiology; radiation related neoplasm /cancer; radiation sensitivity; stem cell transplantation; therapy adverse effect; tobacco abuse; ultraviolet radiation

DESCRIPTION (provided by applicant): Hemopoietic stem cell transplant (HSCT) now offers curative therapy for a number of malignant and non-malignant disorders. However, survivors are at high risk for long-term adverse sequelae, including the development of second malignant neoplasms (SMNs). The etiology of SMNs is thought to involve genetic, treatment and environmental risk factors. HSCT patients are exposed to pretransplant chemotherapy or radiotherapy, to a cytotoxic preparative regimen and to immunosuppressive therapy. Patients may also be exposed to environmental carcinogens, such as UV light or tobacco, components of which are associated with increased risk of primary, and presumably SMNs. A large cohort (N=5806), with 381 patients with SMNs, treated at the Fred Hutchinson Cancer Research Center (FHCRC) is available for study. We have pertinent demographic and treatment information and stored pre-transplant biospecimens on patients, donors and family members. Follow-up is updated on an annual basis. We hypothesize that SMNs following HSCT occur in genetically predisposed individuals. Such predisposition may include increased radiation sensitivity of normal tissue and specific polymorphisms in enzymes related to tobacco metabolism, provision ofnucleotides and DNA repair. In patients with SMNs and in controls without SMN, treated with TBI, matched by race, primary diagnosis and who survived at least the elapsed period between the HSCT and the SMN of the case, we will: 1) investigate radiation sensitivity using in vitro chromosomal breakage assays on B-cell lymphoblastoid cell lines derived from cryopreserved pretransplant peripheral blood mononuclear cells; 2) examine polymorphisms in XRCC1, XRCC3, XPD, and XPG (DNA repair),methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) (folate metabolism), and glutathione-S-transferases (GSTT1, GSMT1, GSTM3, GSTP1) (tobacco metabolism/DNA repair) and microsomal epoxide hydrolase (mEH) (tobacco metabolism); 3) compare allelic frequencies between cases, controls and their first-degree relatives; 4) collect family history, tobacco use and UV light exposure information from self-report questionnaires, and explore relationship to genotype data. The information obtained from this research will provide insight into the role of common inherited variability in modifying susceptibility to SMN. As we learn more about the contributions of, and interactions among genetic susceptibility to second cancers and environmental risk factors, we can develop targeted preventive strategies for those recognized to be at highest risk.

描述（由申请人提供）：造血干细胞移植（HSCT）现在为许多恶性和非恶性疾病提供治愈性治疗。然而，幸存者面临长期不良后遗症的高风险，包括发展为第二恶性肿瘤（SMN）。 SMN 的病因被认为涉及遗传、治疗和环境风险因素。 HSCT 患者接受移植前化疗或放疗、细胞毒性准备方案和免疫抑制治疗。患者还可能接触环境致癌物，例如紫外线或烟草，其中的成分与原发性和可能的​​ SMN 风险增加有关。 Fred Hutchinson 癌症研究中心 (FHCRC) 治疗的大型队列 (N=5806) 包含 381 名 SMN 患者，可供研究。我们拥有相关的人口统计和治疗信息，并存储了患者、捐赠者和家庭成员的移植前生物样本。后续内容每年更新一次。我们假设 HSCT 后的 SMN 发生在有遗传倾向的个体中。这种倾向可能包括正常组织辐射敏感性增加以及与烟草代谢、核苷酸供应和DNA修复相关的酶的特定多态性。对于患有 SMN 的患者和无 SMN 的对照患者，接受 TBI 治疗，按种族、初步诊断匹配，并且至少存活了 HSCT 和病例 SMN 之间的时间间隔，我们将： 1) 使用体外染色体研究辐射敏感性对源自冷冻保存的移植前外周血单核细胞的 B 细胞类淋巴母细胞系进行破碎分析； 2) 检查 XRCC1、XRCC3、XPD 和 XPG（DNA 修复）、亚甲基四氢叶酸还原酶 (MTHFR) 和胸苷酸合成酶 (TS)（叶酸代谢）以及谷胱甘肽-S-转移酶（GSTT1、GSMT1、GSTM3、GSTP1）的多态性（烟草代谢/DNA 修复）和微粒体环氧化物水解酶(mEH)（烟草代谢）； 3) 比较病例、对照及其一级亲属之间的等位基因频率； 4）通过自我报告问卷收集家族史、烟草使用和紫外线暴露信息，并探索与基因型数据的关系。从这项研究中获得的信息将有助于深入了解共同遗传变异在改变 SMN 易感性​​方面的作用。随着我们更多地了解遗传易感性对第二种癌症和环境风险因素的影响和相互作用，我们可以为那些被认为处于最高风险的人制定有针对性的预防策略。