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Grant Details

Grant Number: 3R01CA122838-02S1 Interpret this number
Primary Investigator: Han, Jiali
Organization: Brigham And Women'S Hosp., Inc.
Project Title: Cohort Study of Genetic Susceptibility to Cutaneous Malignant Melanoma
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches; 1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches; 1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Project Narrative: Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies.

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Publications

Replication of associations between GWAS SNPs and melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study.
Authors: Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, Schumacher FR, Kolonel L, Carlson CS, Crawford DC, Goodloe RJ, Dilks H, Baker P, Richardson D, Ambite JL, Song F, Quresh AA, Zhang M, Duggan D, Hutter C, Hindorff LA, Bush WS, Kooperberg C, Le Marchand L, Peters U
Source: J Invest Dermatol, 2014 Jul;134(7), p. 2049-52.
EPub date: 2014 Jan 30.
PMID: 24480881
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A genome-wide association study of severe teenage acne in European Americans.
Authors: Zhang M, Qureshi AA, Hunter DJ, Han J
Source: Hum Genet, 2014 Mar;133(3), p. 259-64.
EPub date: 2013 Oct 11.
PMID: 24114350
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Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk.
Authors: Lin JY, Zhang M, Schatton T, Wilson BJ, Alloo A, Ma J, Qureshi AA, Frank NY, Han J, Frank MH
Source: Biochem Biophys Res Commun, 2013 Jul 5;436(3), p. 536-42.
EPub date: 2013 Jun 12.
PMID: 23770371
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Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans.
Authors: Zhang M, Song F, Liang L, Nan H, Zhang J, Liu H, Wang LE, Wei Q, Lee JE, Amos CI, Kraft P, Qureshi AA, Han J
Source: Hum Mol Genet, 2013 Jul 15;22(14), p. 2948-59.
EPub date: 2013 Apr 1.
PMID: 23548203
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Obesity-related genetic variants, human pigmentation, and risk of melanoma.
Authors: Li X, Liang L, Zhang M, Song F, Nan H, Wang LE, Wei Q, Lee JE, Amos CI, Qureshi AA, Han J
Source: Hum Genet, 2013 Jul;132(7), p. 793-801.
EPub date: 2013 Mar 29.
PMID: 23539184
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A variant in FTO shows association with melanoma risk not due to BMI.
Authors: Iles MM, Law MH, Stacey SN, Han J, Fang S, Pfeiffer R, Harland M, Macgregor S, Taylor JC, Aben KK, Akslen LA, Avril MF, Azizi E, Bakker B, Benediktsdottir KR, Bergman W, ScarrÓ GB, Brown KM, Calista D, Chaudru V, Fargnoli MC, Cust AE, Demenais F, de Waal AC, D?bniak T, Elder DE, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Ho?evar M, H÷iom V, Hopper JL, Ingvar C, Janssen M, Jenkins MA, Kanetsky PA, Kiemeney LA, Lang J, Lathrop GM, Leachman S, Lee JE, Lubi?ski J, Mackie RM, Mann GJ, Martin NG, Mayordomo JI, Molven A, Mulder S, Nagore E, Novakovi? S, Okamoto I, Olafsson JH, Olsson H, Pehamberger H, Peris K, Grasa MP, Planelles D, Puig S, Puig-Butille JA, Randerson-Moor J, Requena C, Rivoltini L, Rodolfo M, Santinami M, Sigurgeirsson B, Snowden H, Song F, Sulem P, Thorisdottir K, Tuominen R, Van Belle P, van der Stoep N, van Rossum MM, Wei Q, Wendt J, Zelenika D, Zhang M, Landi MT, Thorleifsson G, Bishop DT, Amos CI, Hayward NK, Stefansson K, Bishop JA, Barrett JH, GenoMEL Consortium, Q-MEGA and AMFS Investigators
Source: Nat Genet, 2013 Apr;45(4), p. 428-32, 432e1.
EPub date: 2013 Mar 3.
PMID: 23455637
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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.
PMID: 23291271
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Exonuclease 1 (EXO1) gene variation and melanoma risk.
Authors: Song F, Qureshi AA, Zhang J, Amos CI, Lee JE, Wei Q, Han J
Source: DNA Repair (Amst), 2012 Mar 1;11(3), p. 304-9.
EPub date: 2012 Jan 9.
PMID: 22230721
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No association between Parkinson disease alleles and the risk of melanoma.
Authors: Meng S, Song F, Chen H, Gao X, Amos CI, Lee JE, Wei Q, Qureshi AA, Han J
Source: Cancer Epidemiol Biomarkers Prev, 2012 Jan;21(1), p. 243-5.
EPub date: 2011 Nov 15.
PMID: 22086882
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Shorter telomeres associate with a reduced risk of melanoma development.
Authors: Nan H, Du M, De Vivo I, Manson JE, Liu S, McTiernan A, Curb JD, Lessin LS, Bonner MR, Guo Q, Qureshi AA, Hunter DJ, Han J
Source: Cancer Res, 2011 Nov 1;71(21), p. 6758-63.
EPub date: 2011 Oct 25.
PMID: 22028319
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Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma.
Authors: Zhang M, Liang L, Morar N, Dixon AL, Lathrop GM, Ding J, Moffatt MF, Cookson WO, Kraft P, Qureshi AA, Han J
Source: Hum Genet, 2012 Apr;131(4), p. 615-23.
EPub date: 2011 Oct 18.
PMID: 22006220
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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.
PMID: 21993562
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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-ScarrÓ 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, H÷iom V, Hopper JL, Ingvar C, Janssen B, Jenkins MA, J÷nsson 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.
PMID: 21983787
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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-ScarrÓ 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.
PMID: 21983785
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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.
PMID: 21700618
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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.
PMID: 21478494
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A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus.
Authors: Han J, Qureshi AA, Nan H, Zhang J, Song Y, Guo Q, Hunter DJ
Source: Cancer Res, 2011 Mar 1;71(5), p. 1533-9.
EPub date: 2011 Jan 26.
PMID: 21270109
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ASIP genetic variants and the number of non-melanoma skin cancers.
Authors: Lin W, Qureshi AA, Kraft P, Nan H, Guo Q, Hu FB, Jensen MK, Han J
Source: Cancer Causes Control, 2011 Mar;22(3), p. 495-501.
EPub date: 2011 Jan 9.
PMID: 21221757
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Genetic variants in telomere-maintaining genes and skin cancer risk.
Authors: Nan H, Qureshi AA, Prescott J, De Vivo I, Han J
Source: Hum Genet, 2011 Mar;129(3), p. 247-53.
EPub date: 2010 Nov 30.
PMID: 21116649
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Genetic variation in DNA repair pathway genes and melanoma risk.
Authors: Zhang M, Qureshi AA, Guo Q, Han J
Source: DNA Repair (Amst), 2011 Jan 2;10(1), p. 111-6.
EPub date: 2010 Sep 15.
PMID: 20837404
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Polymorphisms in genes involved in oxidative stress and their interactions with lifestyle factors on skin cancer risk.
Authors: He C, Qureshi AA, Han J
Source: J Dermatol Sci, 2010 Oct;60(1), p. 54-6.
EPub date: 2010 Jul 15.
PMID: 20727719
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ABO blood group and incidence of skin cancer.
Authors: Xie J, Qureshi AA, Li Y, Han J
Source: PLoS One, 2010 Aug 4;5(8), p. e11972.
EPub date: 2010 Aug 4.
PMID: 20694147
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Genetic variants in the 53BP1 gene and skin cancer risk.
Authors: He C, Nan H, Qureshi AA, Han J
Source: J Invest Dermatol, 2010 Dec;130(12), p. 2850-3.
EPub date: 2010 Aug 5.
PMID: 20686496
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Polymorphisms of FAS and FAS ligand genes and risk of skin cancer.
Authors: Qureshi A, Nan H, Dyer M, Han J
Source: J Dermatol Sci, 2010 Apr;58(1), p. 78-80.
EPub date: 2010 Jan 25.
PMID: 20219325
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Melanoma susceptibility variants on chromosome 20q11.22 are associated with pigmentary traits and the risk of nonmelanoma skin cancer.
Authors: Nan H, Qureshi AA, Han J
Source: Br J Dermatol, 2010 Feb 1;162(2), p. 461-3.
EPub date: 2009 Nov 30.
PMID: 19995372
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