DNA Repair, Skin Cancer and Overall Cancer Risk

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相关。这一观察结果的基础尚不清楚，但随后发生非皮肤癌的风险表明了高癌症风险表型。一个可能的候选人潜在的这种易感性，皮肤和非皮肤恶性肿瘤是个体间的差异，DNA修复。由于核苷酸切除修复（NER）和NMSC之间的紧密联系，以及大体积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通路基因的多态性可能是潜在的易感性 因子我们将在一项前瞻性队列研究（CLUE II）中检验这一假设，该研究对28，594人进行了19年（至2009年）的癌症发生随访。将对该队列的26个NER基因的75个多态性进行基因分型（使用1989年基线时收集的血液）。具体目标是解决NER途径中的遗传改变和NMSC历史对随后的非NMSC癌症的联合作用。使用事件发生时间分析，将在有和没有NMSC个人病史的患者中评估NER基因型对癌症风险的影响。除了单倍型分析，一种新的统计方法，逻辑回归，将被用来全面评估潜在的相互作用NER途径。这项拟议的研究建立在来自队列中一个个体子集的试点数据基础上，表明具有ERCC 2的NMSC病史的人随后患癌症的风险增加。XPD Lys 751 Gln Lys/Gln或Gln/Gln基因型。基于强有力的科学依据，该假设将高癌症风险NMSC表型的流行病学观察与NER途径中的遗传变异联系起来。使用前瞻性队列研究的方法比病例对照研究具有明显的优势。预期结果的转化将导致更好地确定应考虑采取预防干预措施的高危人群。

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.