Radiation Sensitivity, DNA Repair and Second Cancers

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，幸存者长期不良后遗症的风险很高，包括发生第二次恶性肿瘤（SMN）。SMN的病因被认为涉及遗传、治疗和环境风险因素。HSCT患者暴露于移植前化疗或放疗、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SMN风险增加相关。在Fred哈钦森癌症研究中心（FHCRC）接受治疗的381例SMN患者的大型队列（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、捐赠者和家庭成员的移植前生物标本。每年更新后续行动。我们假设HSCT后SMNs发生在遗传易感个体中。这种易感性可能包括正常组织的辐射敏感性增加和与烟草代谢、核苷酸供应和DNA修复相关的酶的特异性多态性。在患有SMN的患者和没有SMN的对照中，接受TBI治疗，种族、初步诊断匹配，并且至少存活了病例的HSCT和SMN之间的时间段，我们将：1）使用来自冷冻保存的移植前外周血单核细胞的B细胞淋巴母细胞系的体外染色体断裂测定来研究辐射敏感性; 2）检测XRCC 1、XRCC 3、XPD和XPG的多态性（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）和谷胱甘肽-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）; 3）比较病例组、对照组及其一级亲属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，并探讨与基因型数据的关系。从这项研究中获得的信息将提供深入了解常见的遗传变异性在改变SMN易感性中的作用。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贡献和相互作用，我们可以为那些被认为是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.