Genetic Predictors for DNA Repair Phenotype in CMM

描述(申请人提供)：皮肤恶性黑色素瘤(CMM)是最严重的皮肤癌形式。长期以来，阳光一直被怀疑是引起CMM的原因。据预测，由于平流层臭氧浓度的持续下降和日光浴等与阳光相关的娱乐活动的休闲时间增加，CMM的发生率将继续增加，这将增加对太阳紫外线B辐射的暴露，而紫外线B辐射会导致人体DNA损伤。我们最近完成的病例对照研究提供了证据，证明紫外线诱导的DNA损伤的DNA低修复(通过宿主细胞再激活(HCR)试验测量)可能有助于普通人群中的散发性CMM。这7个着色性干皮病基因(XPA、XPB/切除修复交叉互补组3(ERCC3)、XPC、XPD/ERCC2、XPE/受损DNA结合蛋白(DDB1)、XPF/ERCC4和XPG/ERCC5)编码参与核苷酸切除修复(NER)途径的核心蛋白，NER途径有效地修复紫外线损伤的DNA，包括光产物环丁烷嘧啶二聚体(CPDS)和(6-4)光产物(6-4pps)。我们的初步数据表明，XPC和XPD的联合基因型可以预测通过HCR检测的DNA修复表型。我们建议使用病例系列分析来确定这七个NER基因的功能性多态的组合，它们可以预测CMM的DNA修复表型。我们的具体目标是：1.通过采集血样建立800例CMM病例系列，并建立一个完整的流行病学危险因素评估、全身皮肤检查以及NER的基因和表型生物标志物的综合数据库。目的2.确定CMM患者NER的表型和基因特征；目的3.确定DNA修复基因与表型的相关性，寻找最能预测DNA修复表型的NER途径联合基因。这些目标是可以实现的，因为DRC可能是由参与NER的基因的遗传多态决定的，DRC是由DRC测量的。我们的初步数据显示，患有次优DRC的个体有患CMM的风险，XPC和XPD三个多态的联合基因是DRC表型的合理预测因子。由于表型DNA修复试验需要有活细胞的细胞培养，并且对于大分子流行病学研究来说过于劳动密集型，因此识别预测这种DNA修复表型的基因标记非常重要，以便它们可以用于未来在普通人群中筛选具有CMM遗传易感性的个体。当代表CMM遗传易感性的NER基因组合被鉴定并在普通人群中被确认时，它可能会对CMM的一级预防产生重大影响。

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma (CMM) is the most serious form of skin cancer. Sunlight has for a long time been suspected to cause CMM. It is predicted that the incidence of CMM will continue to increase as a result of the continuous decrease in the concentration of stratospheric ozone and increased leisure time for sunlight-related recreations such as sunbathing, which will increase exposure to solar ultraviolet (UV) B radiation responsible for inducing DNA damage in humans. Our recently completed case-control study provides evidence that low DNA repair for UV-induced DNA damage (as measured by a host-cell reactivation (HCR) assay) may contribute to sporadic CMM in the general population. These seven xeroderma pigmentosum (XP) genes (i.e., XPA, XPB/excision repair cross-complementing group 3 (ERCC3), XPC, XPD/ERCC2, XPE/damaged DNA-binding protein (DDB1), XPF/ERCC4 and XPG/ERCC5)code for core proteins involved in the nucleotide excision repair (NER) pathway that effectively repairs UV-damaged DNA including photoproducts such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs). Our preliminary data suggest that a combined genotype of XPC and XPD predicts DNA repair phenotype as measured by the HCR assay. We propose to identify a combination of functional polymorphisms of these seven NER genes that predicts DNA repair phenotype in CMM using a case series analysis. Our specific Aims are: Aim 1. To accrue a case series of 800 incident CMM with blood sample collection and to develop a comprehensive database of complete assessment of epidemiological risk factors, whole body skin examination, and genotypic and phenotypic biomarkers for the NER. Aim 2. To determine phenotypic and genotypic characteristics of NER in these CMM patients; and Aim 3. To determine the correlation between DNA repair genotype and phenotype and identify a combined NER pathway genotype that best predicts the DNA repair phenotype. These aims are achievable, because it is biologically plausible that DRC may be determined by genetic polymorphisms of genes that participate in NER, which is measured by DRC. Our preliminary data have shown that individuals with suboptimal DRC are at risk of developing CMM and that a combined genotype of three polymorphisms of XPC and XPD is a reasonable predictor of the DRC phenotype. Because the phenotypic DNA repair assay requires cell cultures with viable cells and is too labor-intensive for large molecular epidemiological studies, it is important to identify genotypic markers that predict such DNA repair phenotype so that they can be used for future screening for individuals with genetic susceptibility to development of CMM in the general population. When the combined NER genotype representing genetic susceptibility to CMM is identified and is confirmed in the general population, it may have a significant impact on primary prevention of CMM.