Radiation Sensitivity, DNA Repair and Second Cancers

描述（由申请人提供）：造血干细胞移植（HSCT）目前为许多恶性和非恶性疾病提供了治疗方法。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）。SMNs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、细胞毒性预备方案和免疫抑制治疗。患者也可能暴露于环境致癌物，如紫外线或烟草，其成分与原发性和可能的SMNs风险增加有关。在Fred Hutchinson癌症研究中心（FHCRC）接受治疗的381例SMNs患者的大队列（N=5806）可用于研究。我们有相关的人口统计和治疗信息，并储存了患者、捐赠者和家属的移植前生物标本。跟进情况每年更新一次。我们假设HSCT后的smn发生在遗传易感个体中。这种倾向可能包括正常组织的辐射敏感性增加，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。在有SMN的患者和没有SMN的对照组中，接受创伤性脑损伤治疗，根据种族匹配，初次诊断，并且在HSCT和SMN之间至少经过一段时间后存活，我们将：1)使用体外染色体断裂法研究辐射敏感性，这些细胞来自冷冻保存的移植前外周血单个核细胞；2)检测XRCC1、XRCC3、XPD和XPG （DNA修复）、亚甲基四氢叶酸还原酶（MTHFR）和胸腺苷酸合成酶（TS）（叶酸代谢）、谷胱甘肽s转移酶（GSTT1、GSMT1、GSTM3、GSTP1）（烟草代谢/DNA修复）和微粒体环氧化物水解酶（mEH）（烟草代谢）的多态性；3)比较病例、对照组及其一级亲属间的等位基因频率；4)通过自述问卷收集家族史、吸烟情况和紫外线暴露信息，并探讨与基因型数据的关系。从这项研究中获得的信息将深入了解共同遗传变异性在改变SMN易感性方面的作用。随着我们对第二种癌症的遗传易感性和环境风险因素的贡献和相互作用的了解越来越多，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。

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.