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）的个人病史与随后患非皮肤恶性肿瘤以及皮肤癌和粘膜癌的风险增加有关。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存在高癌症风险表型。造成皮肤和非皮肤恶性肿瘤易感性的一个可能原因是个体间DNA修复的差异。由于核苷酸切除修复 (NER) 和 NMSC 之间的密切联系，并且由于大体积 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。我们假设 NER 通路中基因的多态性可能是潜在的易感性 因素。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 人进行了为期 19 年（截至 2009 年）癌症发生情况的跟踪调查。该队列将对 26 个 NER 基因的 75 个多态性进行基因分型（使用 1989 年基线时采集的血液）。具体目标是解决 NER 通路中的遗传改变和 NMSC 历史对随后的非 NMSC 癌症的共同作用。通过时间-事件分析，将评估有或没有 NMSC 个人病史的人的 NER 基因型对癌症风险的影响。除了单倍型分析之外，还将使用一种新的统计方法（逻辑回归）来全面评估 NER 通路内的潜在相互作用。拟议的研究建立在来自队列中一部分个体的试点数据的基础上，这些数据表明有 NMSC 病史且具有 ERCC2./XPD Lys751GIn Lys/GIn 或 Gin/Gin 基因型的人随后患癌症的风险增加。该假说基于强有力的科学原理，将高癌症风险 NMSC 表型的流行病学观察与 NER 通路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。预期结果的转化将有助于更好地识别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.