Role of Genetic Susceptibility in Therapy-related Subsequent Malignancies

遗传易感性在治疗相关的后续恶性肿瘤中的作用

• 批准号: 7800992
• 负责人: SMITA BHATIA
• 金额: $ 70.86万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800992
• 关键词: Acute Myelocytic Leukemia; Adult; Adverse event; Aftercare; Alkylating Agents; Area; Behavior Therapy; Biological; Breast; Cancer Patient; Cancer Survivor; Candidate Disease Gene; Case-Control Studies; Cessation of life; Chemoprevention; Child; Children' s Oncology Group; Chronic; Cities; Cytogenetics; Development; Diagnosis; Drug Transport; Dysmyelopoietic Syndromes; Enzymes; Etiology; Future; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Growth; Health; High-Risk Cancer; Histologic; Hodgkin Disease; Incidence; Individual; Intervention; Ionizing radiation; Joints; Life; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of thyroid; Medical center; Morbidity - disease rate; Odds Ratio; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Predisposition; Prevention; Prevention strategy; Preventive Intervention; Primary Prevention; Protocols documentation; Radiation; Radiation therapy; Relapse; Research Design; Review Literature; Risk; Role; Screening procedure; Second Primary Cancers; Secondary Prevention; Solid; Survival Rate; Survivors; Susceptibility Gene; Testing; Therapeutic; Therapeutic Effect; Topoisomerase-II Inhibitor; Variant; Vulnerable Populations; base; cancer therapy; case control; chemotherapeutic agent; chemotherapy; drug metabolism; gene environment interaction; gene repair; genetic variant; high risk; innovation; leukemia; mortality; neoplasm chemotherapy; premature; public health relevance; radiation effect; repaired; response; therapy development; treatment strategy

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).

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％。癌症幸存者严重或威胁生命的慢性健康状况的累积发生率超过30年的40％。这产生了理解这些不利条件的病因的义务，以制定有针对性的预防/干预策略并降低长期发病率。随后的恶性肿瘤（SMN）是癌症幸存者面临的最具破坏性的不良事件之一，是非复发死亡率的主要原因。但是，在化学放疗和SMN之间存在明确的关联（例如化学疗法和治疗相关的白血病；霍奇金淋巴瘤后的乳腺癌和随后的乳腺癌或甲状腺癌），存在大量的个体间变异性，这可以通过遗传易感性来解释，这可以通过遗传易感性来解释。我们已经成功建立了一种机制，以识别大量具有SMN的癌症幸存者（案例：n = 1600）和没有SMN的癌症幸存者（对照：n = 3200）。我们还实施了协议，以获取详细的治疗摘要并从病例和对照中获取DNA。使用病例对照研究设计，该应用将通过检查特定候选基因中的多态性与SMN的风险来探讨遗传敏感性的作用。由于SMN与特定化学疗法和电离辐射之间的明确关系，重点将放在编码DNA修复途径中的药物代谢酶，药物转运蛋白基因和基因的基因上。基于广泛的文献综述以及对参与DNA修复的生物途径的研究，以及与SMN相关的药物代谢和化学治疗剂的运输基因，在参与DNA修复中涉及的66个基因中的771种多态性以及228个在药物代谢/运输中涉及的228个多态性的基因。该应用检验了与治疗相关的SMN风险与特定治疗暴露，药物代谢基因的变异，药物转运基因，DNA修复基因以及与这些易感基因的特定治疗性暴露的关节作用有关的假设。该应用将检查治疗性暴露和基因的主要影响SMN的风险及其组织学和细胞遗传学亚型，还将检查基因基因和基因环境相互作用在SMN发育中的作用。该应用程序的创新在于使用一种全面且具有生物学上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。该应用将增强我们对SMN发病机理的理解，并促进高危癌症幸存者以开发SMN，进而促进初级预防（未来癌症人群中的个体化治疗）和二次预防（有针对性的筛查，行为修改，在幸存者中进行化学预防）。相关基因和途径的鉴定将提供有关SMN发病机理的关键信息，并可能应用于从头癌。 公共卫生相关性：第二癌是癌症幸存者面临的最具破坏性的长期并发症之一，对于这种脆弱的人群来说，这是过早死亡的普遍原因。该应用旨在了解遗传易感性在第二癌发展中的作用。完成后，该应用将增强我们对第二癌的发病机理的理解，并促进高危生存者以开发SMN，进而促进初级预防（未来癌症种群中的个性化治疗）和二次预防（目标筛查，行为修改，在幸存者中进行化学选择）。