Genetic Predictors for DNA Repair Phenotype in CMM

描述（由申请人提供）：皮肤恶性黑色素瘤（CMM）是最严重的皮肤癌。长期以来，阳光一直被怀疑是导致CMM的原因。据预测，由于平流层臭氧浓度的持续下降以及日光浴等与阳光有关的娱乐活动的休闲时间增加，CMM的发病率将继续增加，这将增加对导致人类DNA损伤的太阳紫外线（UV）B辐射的暴露。我们最近完成的病例对照研究提供的证据表明，低DNA修复紫外线诱导的DNA损伤（通过宿主细胞再活化（HCR）测定）可能有助于散发性CMM在一般人群中。这七个着色性干皮病（XP）基因（即，XPA、XPB/切除修复交叉互补组3（ERCC 3）、XPC、XPD/ERCC 2、XPE/受损DNA结合蛋白（DDB 1）、XPF/ERCC 4和XPG/ERCC 5）编码参与核苷酸切除修复（NER）途径的核心蛋白，所述核苷酸切除修复（NER）途径有效修复UV损伤的DNA，包括光产物如环丁烷嘧啶二聚体（CPD）和（6-4）光产物（6- 4PP）。我们的初步数据表明，XPC和XPD的组合基因型预测DNA修复表型，通过HCR测定。我们建议确定这七个NER基因的功能多态性的组合，预测DNA修复表型在CMM使用的病例系列分析。我们的具体目标是：目标1。收集800例事件CMM的病例系列，采集血样，并开发一个全面的数据库，对NER的流行病学风险因素、全身皮肤检查以及基因型和表型生物标志物进行全面评估。目标2.确定这些CMM患者NER的表型和基因型特征;目的3.确定DNA修复基因型和表型之间的相关性，并确定一个组合的NER途径基因型，最好地预测DNA修复表型。这些目标是可以实现的，因为从生物学上看，DRC可能是由参与NER的基因的遗传多态性决定的，而NER是由DRC测量的。我们的初步数据表明，次优DRC的个人有发展CMM的风险，并且XPC和XPD的三种多态性的组合基因型是DRC表型的合理预测因子。由于表型DNA修复测定需要具有活细胞的细胞培养物，并且对于大规模分子流行病学研究来说过于劳动密集型，因此重要的是鉴定预测这种DNA修复表型的基因型标记，使得它们可以用于将来筛选在一般人群中对CMM发展具有遗传易感性的个体。当代表CMM遗传易感性的联合NER基因型在一般人群中被鉴定和确认时，它可能对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.