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，阳光一直被怀疑是造成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有关的休闲活动的增加，CMM的发病率将继续增加，这将增加暴露于导致人类DNA损伤的太阳紫外线（UV） B辐射。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损伤的低DNA修复（通过宿主细胞再激活（HCR）测定）可能导致普通人群中的散发性CMM。这7个色素干皮病（XP）基因（即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，该途径有效修复紫外线损伤的DNA，包括环丁烷嘧啶二聚体（CPDs）和（6-4）光产物（6-4PPs）。我们的初步数据表明，通过HCR测定，XPC和XPD的组合基因型预测DNA修复表型。我们建议使用病例序列分析来确定这七个NER基因的功能多态性组合，这些基因可以预测CMM中的DNA修复表型。我们的具体目标是：目标1。收集800例CMM病例，并收集血样，建立一个全面的数据库，全面评估流行病学危险因素、全身皮肤检查以及NER的基因型和表型生物标志物。目标2。目的：确定慢性粒细胞白血病患者肾内肾的表型和基因型特征；和Aim 3。确定DNA修复基因型与表型之间的相关性，并确定最能预测DNA修复表型的NER通路组合基因型。这些目标是可以实现的，因为DRC可能由参与NER的基因的遗传多态性决定，这在生物学上是合理的，这是由DRC测量的。我们的初步数据表明，具有次优DRC的个体有发生CMM的风险，XPC和XPD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修复试验需要用活细胞进行细胞培养，并且对于大分子流行病学研究来说过于劳动密集型，因此确定预测这种DNA修复表型的基因型标记是很重要的，这样它们就可以用于未来筛查普通人群中对CMM发展具有遗传易感性的个体。当确定并在普通人群中确认代表CMM遗传易感性的NER联合基因型时，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.