Role of Genetic Susceptibility in Therapy-related Subsequent Malignancies

描述（由申请人提供）：到2010年，美国将有1200万癌症幸存者，年增长率为2%。癌症幸存者中严重或危及生命的慢性健康状况的累积发病率在30年时超过40%。这就产生了了解这些不良状况的病因的义务，以便制定有针对性的预防/干预战略并降低长期发病率。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，并且是非复发死亡率的主要原因。尽管放化疗和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的乳腺癌或甲状腺癌），存在相当大的个体间差异，这可以通过潜在的遗传易感性来解释-这是目前研究不足的领域。我们已经成功地建立了一种机制，以确定大量的癌症幸存者与SMN（病例：n=1600）和那些没有（对照组：n=3200）。我们还实施了方案，以获得详细的治疗总结，并从病例和对照组中获得DNA。使用病例对照研究设计，本申请将通过检查特定候选基因的多态性与SMN风险之间的关联来探索遗传易感性的作用。由于SMNs和特定的化疗和电离辐射之间的明确关系，重点将放在编码药物代谢酶的基因，药物转运基因和DNA修复途径中的基因。基于广泛的文献综述以及对DNA修复中涉及的生物学途径以及SMN中涉及的化疗药物代谢和转运的基因的研究，选择了66个DNA修复基因中的771个多态性和35个药物代谢/转运基因中的228个多态性。该申请检验了以下假设：治疗相关SMN的风险与特定治疗暴露、药物代谢基因、药物转运基因、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效应相关。该应用程序将检查治疗暴露和基因对SMN及其组织学和细胞遗传学亚型风险的主要影响，还将检查基因-基因和基因-环境相互作用在SMN发展中的作用。该应用的创新在于使用全面的和生物学上合理的候选基因方法来检查与SMN相关的众所周知的治疗暴露相结合的遗传变异。该应用将增强我们对SMN发病机制的理解，并有助于识别处于SMN发展高风险的癌症幸存者，从而促进一级预防（未来癌症人群的个体化治疗）和二级预防（幸存者的靶向筛查，行为矫正，化学预防）。相关基因和途径的鉴定将提供有关SMN发病机制的关键信息，并可能应用于新发癌症。 公共卫生相关性：其次，癌症是癌症幸存者面临的最具破坏性的长期并发症之一，也是这一弱势群体过早死亡的常见原因。该应用旨在了解遗传易感性在第二种癌症发展中的作用。该应用程序完成后，将提高我们对第二种癌症发病机制的理解，并促进识别SMN发展的高风险幸存者，从而促进一级预防（未来癌症人群的个体化治疗）和二级预防（幸存者的靶向筛查，行为矫正，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).