Role of Genetic Susceptibility in Therapy-related Subsequent Malignancies

描述(申请人提供)：到2010年，美国将有1200万癌症幸存者，年增长率为2%。癌症幸存者的严重或危及生命的慢性健康状况的累积发生率在30年后超过40%。这就产生了了解这些不利条件的病因的义务，以便制定有针对性的预防/干预战略，减少长期发病率。后续恶性肿瘤(SMN)是癌症幸存者面临的最具破坏性的不良事件之一，也是导致无复发死亡的主要原因。尽管化疗和放射治疗与SMN之间存在明确的相关性(例如，化疗和治疗相关的白血病；电离辐射和霍奇金淋巴瘤后继发的乳腺癌或甲状腺癌)，但个体间存在相当大的差异性，这可以用潜在的遗传易感性来解释--这一领域目前研究不足。我们已经成功地建立了一种机制来识别大量患有SMN的癌症幸存者(病例：1600例)和未患SMN的癌症幸存者(对照：N=3200例)。我们还执行了协议，以获得详细的治疗总结，并从病例和对照中获取DNA。使用病例对照研究设计，这项应用将通过检查特定候选基因的多态与SMN风险之间的关联，来探索遗传易感性的作用。由于SMN与特定的化疗和电离辐射有明确的关系，因此重点将放在编码药物代谢酶的基因、药物转运体基因和DNA修复途径基因上。在广泛的文献综述和对参与DNA修复的生物学途径以及参与药物代谢和药物转运的基因研究的基础上，筛选出与DNA修复相关的66个基因中的771个多态性，以及参与药物代谢/转运的35个基因中的228个多态性。该应用测试了以下假设：与治疗相关的SMN的风险与特定的治疗暴露、药物代谢基因、药物运输基因、DNA修复基因的变异以及特定治疗暴露与这些易感基因的联合作用有关。该应用程序将检查治疗暴露和SMN风险基因及其组织学和细胞遗传学亚型的主要影响，并将检查基因-基因和基因-环境相互作用在SMN发展中的作用。这项应用的创新之处在于使用一种全面的、在生物学上看似合理的候选基因方法来检查遗传变异，并结合与SMN相关的众所周知的治疗暴露。该应用将加深我们对SMN发病机制的了解，并有助于识别癌症幸存者发展为SMN的高危人群，进而促进一级预防(未来癌症人群的个体化治疗)和二级预防(有针对性的筛查、行为矫正、幸存者的化学预防)。相关基因和途径的识别将为SMN的发病机制提供关键信息，并有可能应用于新生癌症。 公共卫生相关性：第二癌症是癌症幸存者面临的最具破坏性的长期并发症之一，也是这一脆弱人群过早死亡的常见原因。这项应用旨在了解遗传易感性在第二种癌症发展中的作用。完成后，该应用程序将增强我们对第二种癌症发病机制的了解，并有助于识别患有SMN的高危幸存者，进而促进一级预防(未来癌症人群的个体化治疗)和二级预防(有针对性的筛查、行为矫正、幸存者的化学预防)。

DESCRIPTION (provided by applicant): By 2010, there will be 12 million cancer survivors in the U.S., with an annual growth rate of 2%. The cumulative incidence of severe or life-threatening chronic health conditions in cancer survivors exceeds 40% at 30 years. This creates an obligation to understand the etiology of these adverse conditions, in order to develop targeted prevention/ intervention strategies and reduce long-term morbidity. Subsequent malignant neoplasms (SMNs) are one of the most devastating adverse events faced by cancer survivors, and are a leading cause of non- relapse mortality. Although, well-defined associations exist between chemoradiotherapy and SMNs (e.g., chemotherapy and therapy-related leukemia; ionizing radiation and subsequent breast or thyroid cancer after Hodgkin lymphoma), there is considerable inter-individual variability, which could be explained by underlying genetic susceptibility - an area that is currently understudied. We have successfully established a mechanism to identify a large number of cancer survivors with SMNs (cases: n=1600) and those without (controls: n=3200). We have also implemented protocols to obtain detailed therapeutic summaries and procure DNA from the cases and controls. Using a case-control study design, this application will explore the role of genetic susceptibility, by examining associations between polymorphisms in specific candidate genes, and the risk of SMN. Because of the well-defined relation between SMNs and specific chemotherapy and ionizing radiation, the focus will be on genes encoding drug metabolizing enzymes, drug-transporter genes, and genes in DNA repair pathways. Based on extensive literature review as well as study of biological pathways involved in DNA repair, and genes involved in drug metabolism and transport of chemotherapeutic agents implicated in SMNs, 771 polymorphisms in 66 genes involved in DNA repair, and 228 polymorphisms in 35 genes involved in drug metabolism/ transport have been selected. The application tests the hypotheses that the risk of treatment-related SMNs is associated with specific therapeutic exposures, variants in drug-metabolizing genes, drug transport genes, DNA repair genes, and the joint effects of specific therapeutic exposures with these susceptibility genes. The application will examine main effects of therapeutic exposures and genes for risk of SMNs and of its histologic and cytogenetic subtypes, and will also examine the role of gene-gene and gene-environment interactions in SMN development. This application's innovation lies in using a comprehensive and biologically plausible candidate gene approach to examine genetic variants in combination with well-known therapeutic exposures associated with SMNs. The application will enhance our understanding of the pathogenesis of SMN, and facilitate identification of cancer survivors at high-risk for development of SMNs, in turn facilitating primary prevention (individualizing therapy in future cancer populations) and secondary prevention (targeted screening, behavior modification, chemoprevention in survivors). Identification of pertinent genes and pathways will provide critical information regarding pathogenesis of SMN, with potential application to de novo cancer. PUBLIC HEALTH RELEVANCE: Second cancers are one of the most devastating long-term complications faced by cancer survivors, and are a common cause of premature death for this vulnerable population. This application aims to understand the role of genetic susceptibility in the development of second cancers. At its completion, the application will enhance our understanding of the pathogenesis of second cancers, and facilitate identification of survivors at high-risk for development of SMNs, in turn facilitating primary prevention (individualizing therapy in future cancer populations) and secondary prevention (targeted screening, behavior modification, chemoprevention in survivors).