|Grant Number:||5R01CA100264-05 Interpret this number|
|Primary Investigator:||Wei, Qingyi|
|Organization:||University Of Tx Md Anderson Can 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.
Genetic variants in Fanconi Anemia Pathway Genes BRCA2 and FANCA Predict Melanoma Survival.
Authors: Yin J, Liu H, Liu Z, Wang LE, Chen WV, Zhu D, Amos CI, Fang S, Lee JE, Wei Q
Source: J Invest Dermatol, 2014 Sep 22;null, p. null.
EPub date: 2014 Sep 22.
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: 2014 Jan 30.
Association of marijuana smoking with oropharyngeal and oral tongue cancers: pooled analysis from the INHANCE consortium.
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A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.
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Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans.
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A variant in FTO shows association with melanoma risk not due to BMI.
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Source: Nat Genet, 2013 Apr;45(4), p. 428-32, 432e1.
EPub date: 2013 Mar 3.
Polymorphisms of nucleotide excision repair genes predict melanoma survival.
Authors: Li C, Yin M, Wang LE, Amos CI, Zhu D, Lee JE, Gershenwald JE, Grimm EA, Wei Q
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EPub date: 2013 Feb 14.
Variants in melanocortin 1 receptor gene contribute to risk of melanoma--a direct sequencing analysis in a Texas population.
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EPub date: 2013 Feb 19.
Association between putative functional variants in the PSMB9 gene and risk of melanoma--re-analysis of published melanoma genome-wide association studies.
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Source: Pigment Cell Melanoma Res, 2013 May;26(3), p. 392-401.
EPub date: 2013 Mar 27.
Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk.
Authors: Liu H, Wang LE, Liu Z, Chen WV, Amos CI, Lee JE, Q-MEGA and AMFS Investigators, GenoMEL Investigators, Iles MM, Law MH, Barrett JH, Montgomery GW, Taylor JC, MacGregor S, Cust AE, Newton Bishop JA, Hayward NK, Bishop DT, Mann GJ, Affleck P, Wei Q
Source: Carcinogenesis, 2013 Apr;34(4), p. 885-92.
EPub date: 2013 Jan 4.
Detectable clonal mosaicism from birth to old age and its relationship to cancer.
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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.
Authors: Liu H, Wei Q, Gershenwald JE, Prieto VG, Lee JE, Duvic M, Grimm EA, Wang LE
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
Source: J Invest Dermatol, 2012 Feb;132(2), p. 485-7.
EPub date: 2011 Oct 13.
Genome-wide association study identifies three new melanoma susceptibility loci.
Authors: Barrett JH, Iles MM, Harland M, Taylor JC, Aitken JF, Andresen PA, Akslen LA, Armstrong BK, Avril MF, Azizi E, Bakker B, Bergman W, Bianchi-Scarrà G, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Corda E, Cust AE, D?bniak T, Duffy D, Dunning AM, Easton DF, Friedman E, Galan P, Ghiorzo P, Giles GG, Hansson J, Hocevar M, Höiom V, Hopper JL, Ingvar C, Janssen B, Jenkins MA, Jönsson G, Kefford RF, Landi G, Landi MT, Lang J, Lubi?ski J, Mackie R, Malvehy J, Martin NG, Molven A, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Pastorino L, Puig S, Puig-Butille JA, Randerson-Moor J, Snowden H, Tuominen R, Van Belle P, van der Stoep N, Whiteman DC, Zelenika D, Han J, Fang S, Lee JE, Wei Q, Lathrop GM, Gillanders EM, Brown KM, Goldstein AM, Kanetsky PA, Mann GJ, Macgregor S, Elder DE, Amos CI, Hayward NK, Gruis NA, Demenais F, Bishop JA, Bishop DT, GenoMEL Consortium
Source: Nat Genet, 2011 Oct 9;43(11), p. 1108-13.
EPub date: 2011 Oct 9.
Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3.
Authors: Macgregor S, Montgomery GW, Liu JZ, Zhao ZZ, Henders AK, Stark M, Schmid H, Holland EA, Duffy DL, Zhang M, Painter JN, Nyholt DR, Maskiell JA, Jetann J, Ferguson M, Cust AE, Jenkins MA, Whiteman DC, Olsson H, Puig S, Bianchi-Scarrà G, Hansson J, Demenais F, Landi MT, D?bniak T, Mackie R, Azizi E, Bressac-de Paillerets B, Goldstein AM, Kanetsky PA, Gruis NA, Elder DE, Newton-Bishop JA, Bishop DT, Iles MM, Helsing P, Amos CI, Wei Q, Wang LE, Lee JE, Qureshi AA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Han J, Hopper JL, Trent JM, Brown KM, Martin NG, Mann GJ, Hayward NK
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.
Authors: Amos CI, Wang LE, Lee JE, Gershenwald JE, Chen WV, Fang S, Kosoy R, Zhang M, Qureshi AA, Vattathil S, Schacherer CW, Gardner JM, Wang Y, Bishop DT, Barrett JH, GenoMEL Investigators, MacGregor S, Hayward NK, Martin NG, Duffy DL, Q-Mega Investigators, Mann GJ, Cust A, Hopper J, AMFS Investigators, Brown KM, Grimm EA, Xu Y, Han Y, Jing K, McHugh C, Laurie CC, Doheny KF, Pugh EW, Seldin MF, Han J, Wei Q
Source: Hum Mol Genet, 2011 Dec 15;20(24), p. 5012-23.
EPub date: 2011 Sep 17.
Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma.
Authors: Nan H, Xu M, Kraft P, Qureshi AA, Chen C, Guo Q, Hu FB, Curhan G, Amos CI, Wang LE, Lee JE, Wei Q, Hunter DJ, Han J
Source: Hum Mol Genet, 2011 Sep 15;20(18), p. 3718-24.
EPub date: 2011 Jun 23.
Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk.
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
Source: Hum Mol Genet, 2011 Jul 1;20(13), p. 2673-9.
EPub date: 2011 Apr 9.
Promoter polymorphisms in matrix metallopeptidase 1 and risk of cutaneous melanoma.
Authors: Wang LE, Huang YJ, Yin M, Gershenwald JE, Prieto VG, Lee JE, Duvic M, Grimm EA, Wei Q
Source: Eur J Cancer, 2011 Jan;47(1), p. 107-15.
EPub date: 2010 Jul 23.
Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.
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Source: Int J Epidemiol, 2010 Aug;39(4), p. 1091-102.
EPub date: 2010 Feb 1.
Marijuana smoking and the risk of head and neck cancer: pooled analysis in the INHANCE consortium.
Authors: Berthiller J, Lee YC, Boffetta P, Wei Q, Sturgis EM, Greenland S, Morgenstern H, Zhang ZF, Lazarus P, Muscat J, Chen C, Schwartz SM, Eluf Neto J, Wünsch Filho V, Koifman S, Curado MP, Matos E, Fernandez L, Menezes A, Daudt AW, Ferro G, Brennan P, Hashibe M
Source: Cancer Epidemiol Biomarkers Prev, 2009 May;18(5), p. 1544-51.
Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.
Authors: Hashibe M, Brennan P, Chuang SC, Boccia S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, Herrero R, Kelsey K, Koifman S, La Vecchia C, Lazarus P, Levi F, Lence JJ, Mates D, Matos E, Menezes A, McClean MD, Muscat J, Eluf-Neto J, Olshan AF, Purdue M, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Shangina O, Pilarska A, Zhang ZF, Ferro G, Berthiller J, Boffetta P
Source: Cancer Epidemiol Biomarkers Prev, 2009 Feb;18(2), p. 541-50.
EPub date: 2009 Feb 3.