|Grant Number:||5R01CA100264-05 Interpret this number|
|Primary Investigator:||Wei, Qingyi|
|Organization:||Ut Md Anderson Cancer Ctr|
|Project Title:||Genetic Predictors for DNA Repair Phenotype in Cmm|
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.
Replication of Associations between GWAS SNPs and Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study.
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EPub date: 2013 Mar 3.
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Source: Nat Genet, 2012 May 6;44(6), p. 642-50.
EPub date: 2012 May 6.
Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression.
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Source: Melanoma Res, 2012 Apr;22(2), p. 169-75.
Meta-analysis combining new and existing data sets confirms that the TERT-CLPTM1L locus influences melanoma risk.
Authors: Law MH, Montgomery GW, Brown KM, Martin NG, Mann GJ, Hayward NK, MacGregor S, Q-MEGA and AMFS Investigators
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EPub date: 2011 Oct 13.
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Source: Nat Genet, 2011 Oct 9;43(11), p. 1114-8.
EPub date: 2011 Oct 9.
Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.
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EPub date: 2011 Jun 23.
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Authors: Nan H, Xu M, Zhang J, Zhang M, Kraft P, Qureshi AA, Chen C, Guo Q, Hu FB, Rimm EB, Curhan G, Song Y, Amos CI, Wang LE, Lee JE, Wei Q, Hunter DJ, Han J
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EPub date: 2011 Apr 9.