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）：血压干细胞移植（HSCT）现在为多种恶性和非恶性疾病提供治疗疗法。但是，幸存者对长期不良后遗症的风险很高，包括第二次恶性肿瘤（SMN）的发展。 SMN的病因被认为涉及遗传，治疗和环境风险因素。 HSCT患者接受了移植前化学疗法或放射疗法，细胞毒性制备方案和免疫抑制治疗。患者还可能暴露于环境致癌物（例如紫外线或烟草）中，其成分与原发性和大概SMN的风险增加有关。可以研究在弗雷德·哈钦森癌症研究中心（FHCRC）治疗的大型队列（n = 5806），有381例SMN患者。我们拥有相关的人口和治疗信息，并对患者，捐助者和家人存储了移植前的生物植物。随访每年更新。我们假设HSCT后的SMN发生在遗传性易感的个体中。这种倾向可能包括正常组织的辐射敏感性和与烟草代谢，核苷酸的提供和DNA修复有关的酶中的特定多态性。 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，对照及其一级亲戚之间的等位基因频率； 4）从自我报告问卷中收集家族史，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洞悉常见的遗传变异性在修改SMN易感性方面的作用。随着我们更多地了解对第二癌和环境风险因素的遗传敏感性的贡献以及相互作用，我们可以为被公认为处于最高风险的人们制定有针对性的预防策略。