Radiation Sensitivity, DNA Repair and Second Cancers

描述(申请人提供)：造血干细胞移植(HSCT)现在为一些恶性和非恶性疾病提供根治疗法。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)。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射治疗，接受细胞毒性准备方案，并接受免疫抑制治疗。患者还可能接触到环境致癌物，如紫外线或烟草，其成分与原发和可能的SMN风险增加有关。在弗雷德·哈钦森癌症研究中心(FHCRC)治疗的381名SMN患者中，有一个大的队列(N=5806)可供研究。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。后续工作每年更新一次。我们假设HSCT后的SMN发生在遗传易感性的个体中。这种易感性可能包括正常组织对辐射的敏感性增加，以及与烟草新陈代谢、核苷酸供应和DNA修复相关的酶的特定多态性。在有SMN的患者和无SMN的对照组中，经TBI治疗，种族、初步诊断相匹配，且至少存活了HSCT和SMN之间的时间段的患者，我们将：1)用体外染色体断裂分析方法研究来自深低温保存的移植前外周血单个核细胞来源的B细胞淋巴母细胞系的辐射敏感性；2)检测XRCC1、XRCC3、XPD和XPG(DNA修复)、亚甲基四氢叶酸还原酶(MTHFR)和胸苷合成酶(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)等位基因的多态性；3)比较病例、对照及其一级亲属的等位基因频率；4)从自填式问卷收集家族史、吸烟和紫外线暴露信息，并探讨与烟草代谢的关系。从这项研究中获得的信息将提供对常见遗传变异在改变SMN易感性方面的作用的洞察。随着我们更多地了解第二次癌症的遗传易感性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.