DNA Repair, Skin Cancer and Overall Cancer Risk

DNA 修复、皮肤癌和总体癌症风险

• 批准号: 6867583
• 负责人: ANTHONY J ALBERG
• 金额: $ 53.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-25 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867583
• 关键词: DNA repair; cancer risk; clinical research; genetic susceptibility; genotype; human subject; longitudinal human study; neoplasm /cancer genetics; single nucleotide polymorphism; skin neoplasms

DESCRIPTION (provided by applicant): A personal history of non-melanoma skin cancer (NMSC) is associated with an increased subsequent risk of both non-cutaneous malignancies and cutaneous and mucosal cancers. The basis for this observation remains unclear, but the risk of subsequent non-skin cancers suggests a high cancer-risk phenotype. A likely candidate underlying this susceptibility to both cutaneous and non-cutaneous malignancies is inter-individual differences in DNA repair. Because of the strong link between Nucleotide Excision Repair (NER) and NMSC, and because of the importance of bulky DNA adducts to all cancers, the NER pathway is the most relevant DNA repair pathway. We hypothesize that polymorphisms in genes in the NER pathway may be the underlying susceptibility factor. We will test this hypothesis in a prospective cohort study (CLUE II) of 28,594 persons who will have been followed-up for 19 years (through 2009) for the occurrence of cancer. The cohort will be genotyped (using blood collected at baseline in 1989) for 75 polymorphisms in 26 NER genes. The specific aim addresses the joint role of genetic alterations in the NER pathway and history of NMSC on subsequent non-NMSC cancer. Using time-to-event analyses, the influence of NER genotypes on cancer risk will be assessed in those with and without a personal history of NMSC. In addition to haplotype analysis, a novel statistical approach, logic regression, will be used to comprehensively assess the potential interactions within the NER pathway. The proposed study builds on pilot data from a subset of individuals in the cohort indicating an increased risk of subsequent cancer in persons with a history of NMSC who had ERCC2./XPD Lys751GIn Lys/GIn or Gin/Gin genotypes. Based on a strong scientific rationale, the hypothesis links an epidemiologic observation of a high cancer-risk NMSC phenotype with genetic variation in the NER pathway. The approach of using a prospective cohort study holds distinct advantages over case-control studies. Translation of the expected results will lead to better identification of at risk populations who should be considered for prevention interventions.

描述(由申请人提供)：非黑色素瘤皮肤癌(NMSC)的个人病史与非皮肤恶性肿瘤以及皮肤和粘膜癌的后续风险增加有关。这一观察的基础尚不清楚，但随后发生非皮肤癌的风险表明存在高癌症风险表型。皮肤和非皮肤恶性肿瘤的易感性可能与DNA修复的个体差异有关。由于核苷酸切除修复(NER)与NMSC之间的密切联系，以及大量DNA加合物对所有癌症的重要性，NER途径是最相关的DNA修复途径。我们推测NER途径中的基因多态可能是潜在的易感性。 因素。我们将在一项前瞻性队列研究(线索II)中验证这一假设，该研究对28,594人进行了19年(到2009年)的癌症发生跟踪调查。该队列将对26个NER基因的75个多态进行基因分型(使用1989年基线采集的血液)。其具体目的在于阐明NER通路中的基因改变和NMSC的病史在随后的非NMSC癌中的联合作用。使用事件发生时间分析，将在有和没有NMSC个人病史的人中评估NER基因对癌症风险的影响。除了单倍型分析，一种新的统计方法，逻辑回归，将被用来全面评估NER通路中的潜在相互作用。这项拟议的研究建立在队列中一部分人的试点数据基础上，这些数据表明，有NMSC病史的人中，具有ERCC2./XPD Lys751GIn Lys/Gin或Gin/Gin基因的人继发癌症的风险增加。基于强大的科学基础，该假说将高癌症风险NMSC表型的流行病学观察与NER途径的遗传变异联系起来。与病例对照研究相比，采用前瞻性队列研究的方法具有明显的优势。转换预期结果将有助于更好地确定应考虑进行预防干预的高危人群。