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Grant Details

Grant Number: 5R01CA088363-10 Interpret this number
Primary Investigator: Hayward, Nicholas
Organization: Queensland Institute Of Medical Research
Project Title: Pathways From Genotype and Environment to Melanoma
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): For 20 years we have conducted large scale studies into the molecular genetics and epidemiology of melanoma and its risk factors, particularly nevus density which is more heritable than melanoma itself and therefore a better target for gene-finding. With NCI funds we recently followed up a population-based sample of 1,911 melanoma probands to update survival status and risk factor information; we have obtained DNA from all melanoma cases and a sample of unaffected relatives, and have done likewise in previously studied samples of melanoma cases in children (<14y), adolescents (14-19y) and older men (>50y). We now have DNA samples and risk factor information on 2,783 members of approximately 1,500 melanoma families. We also have >4000 DNA samples from adolescent twins and their family members for whom we have nevus counts and pigmentary phenotypes. From the latter study we recently published linkage to flat nevus density on 9p, 9q, 2p and 8q, replicated in one or more recent studies from UK, France (FR) and Netherlands (NL). To find causal variants under our linkage peaks and also in the rest of the genome we shall conduct a genomewide association scan for nevus density (GWAS). In Stage 1 we shall genotype extremes of the nevus density distribution (300 highest, 300 lowest, one individual per family) from our adolescent twins with 1 million SNPs using Illumina Hap1M arrays (>90% of the genome covered at r2>0.9). Arrays are enriched for SNPs in regions of copy number variation, which is plausibly implicated in nevus etiology. Different Bonferroni corrected alpha levels will be used to assess significance of the ~10,000 SNPs under our four nominated linkage peaks (5 x 10-6) and those in the rest of the genome (1.7 x 10-7). In Stage 2 the top 200 significant hits in linkage regions, and the top 200 in the rest of the genome will be typed in replication samples from the UK, FR and NL (N~3600) and in 1500 melanoma cases and 1500 controls from our familial melanoma study. In Stage 3, the top ~50 SNPs from a combined analysis of Stages 1 and 2 will be typed in the remainder of the adolescent nevus and familial melanoma studies (N=3,200). We shall perform within-family and case-control analyses for association of melanoma risk variables including status, age-at-onset, survival, and severity, with SNPs and environmental risk factors, stratified by familial risk and anatomic site of the melanoma. Similar analyses will be conducted for mediating variables such as nevus density, freckling, and pigmentation. We shall test for gene-gene interactions (epistasis) between SNPs of nevus genes and melanoma risk, and for gene-environment interactions of nevogenesis SNPs with measures of sun exposure, on melanoma risk. Relevance: A high mole count is the strongest risk factor for melanoma and our study has the power to find 80% of genes with effect sizes as small as 1% of variation in moliness. These in turn will be tested to assess their risk for melanoma, both singly and in combinations with other genetic and environmental risk factors. The costs of melanoma to society are considerable. In 1994, there were over 28,000 new cases of melanoma in the USA and a total of 6,680 people died from this disease. Incidence rates in Queensland are almost five times those in the United States. The aim of our research is to contribute to the alleviation of this disease burden, and it is our assessment that the potential benefits of this research greatly outweigh the costs.

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Publications

Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits.
Authors: Jagirdar K, Smit DJ, Ainger SA, Lee KJ, Brown DL, Chapman B, Zhen Zhao Z, Montgomery GW, Martin NG, Stow JL, Duffy DL, Sturm RA
Source: Pigment Cell Melanoma Res, 2014 Jul;27(4), p. 552-64.
EPub date: 2014 May 12.
PMID: 24739399
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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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A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
Authors: Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, Taylor JC, Duffy DL, Holohan K, Dutton-Regester K, Palmer JM, Bonazzi V, Stark MS, Symmons J, Law MH, Schmidt C, Lanagan C, O'Connor L, Holland EA, Schmid H, Maskiell JA, Jetann J, Ferguson M, Jenkins MA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Whiteman DC, Pharoah PD, Easton DF, Dunning AM, Newton-Bishop JA, Montgomery GW, Martin NG, Mann GJ, Bishop DT, Tsao H, Trent JM, Fisher DE, Hayward NK, Brown KM
Source: Nature, 2011 Nov 13;480(7375), p. 99-103.
EPub date: 2011 Nov 13.
PMID: 22080950
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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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Polymorphisms in nevus-associated genes MTAP, PLA2G6, and IRF4 and the risk of invasive cutaneous melanoma.
Authors: Kvaskoff M, Whiteman DC, Zhao ZZ, Montgomery GW, Martin NG, Hayward NK, Duffy DL
Source: Twin Res Hum Genet, 2011 Oct;14(5), p. 422-32.
PMID: 21962134
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Nevi, family history, and fair skin increase the risk of second primary melanoma.
Authors: Siskind V, Hughes MC, Palmer JM, Symmons JM, Aitken JF, Martin NG, Hayward NK, Whiteman DC
Source: J Invest Dermatol, 2011 Feb;131(2), p. 461-7.
EPub date: 2010 Oct 14.
PMID: 20944647
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Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.
Authors: Demenais F, Mohamdi H, Chaudru V, Goldstein AM, Newton Bishop JA, Bishop DT, Kanetsky PA, Hayward NK, Gillanders E, Elder DE, Avril MF, Azizi E, van Belle P, Bergman W, Bianchi-ScarrÓ G, Bressac-de Paillerets B, Calista D, Carrera C, Hansson J, Harland M, Hogg D, H÷iom V, Holland EA, Ingvar C, Landi MT, Lang JM, Mackie RM, Mann GJ, Ming ME, Njauw CJ, Olsson H, Palmer J, Pastorino L, Puig S, Randerson-Moor J, Stark M, Tsao H, Tucker MA, van der Velden P, Yang XR, Gruis N, Melanoma Genetics Consortium
Source: J Natl Cancer Inst, 2010 Oct 20;102(20), p. 1568-83.
EPub date: 2010 Sep 28.
PMID: 20876876
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IRF4 variants have age-specific effects on nevus count and predispose to melanoma.
Authors: Duffy DL, Iles MM, Glass D, Zhu G, Barrett JH, H÷iom V, Zhao ZZ, Sturm RA, Soranzo N, Hammond C, Kvaskoff M, Whiteman DC, Mangino M, Hansson J, Newton-Bishop JA, GenoMEL, Bataille V, Hayward NK, Martin NG, Bishop DT, Spector TD, Montgomery GW
Source: Am J Hum Genet, 2010 Jul 9;87(1), p. 6-16.
EPub date: 2010 Jun 17.
PMID: 20602913
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Digital quantification of human eye color highlights genetic association of three new loci.
Authors: Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, Park D, Zhu G, Larsson M, Duffy DL, Montgomery GW, Mackey DA, Walsh S, Lao O, Hofman A, Rivadeneira F, Vingerling JR, Uitterlinden AG, Martin NG, Hammond CJ, Kayser M
Source: PLoS Genet, 2010 May 6;6(5), p. e1000934.
EPub date: 2010 May 6.
PMID: 20463881
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Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma.
Authors: Duffy DL, Zhao ZZ, Sturm RA, Hayward NK, Martin NG, Montgomery GW
Source: J Invest Dermatol, 2010 Feb;130(2), p. 520-8.
EPub date: 2009 Aug 27.
PMID: 19710684
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Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi.
Authors: Falchi M, Bataille V, Hayward NK, Duffy DL, Bishop JA, Pastinen T, Cervino A, Zhao ZZ, Deloukas P, Soranzo N, Elder DE, Barrett JH, Martin NG, Bishop DT, Montgomery GW, Spector TD
Source: Nat Genet, 2009 Aug;41(8), p. 915-9.
EPub date: 2009 Jul 5.
PMID: 19578365
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Genome-wide association study identifies three loci associated with melanoma risk.
Authors: Bishop DT, Demenais F, Iles MM, Harland M, Taylor JC, Corda E, Randerson-Moor J, Aitken JF, Avril MF, Azizi E, Bakker B, Bianchi-ScarrÓ G, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Chin-A-Woeng T, Debniak T, Galore-Haskel G, Ghiorzo P, Gut I, Hansson J, Hocevar M, H÷iom V, Hopper JL, Ingvar C, Kanetsky PA, Kefford RF, Landi MT, Lang J, Lubi?ski J, Mackie R, Malvehy J, Mann GJ, Martin NG, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Puig S, Weiss M, van Workum W, Zelenika D, Brown KM, Goldstein AM, Gillanders EM, Boland A, Galan P, Elder DE, Gruis NA, Hayward NK, Lathrop GM, Barrett JH, Bishop JA
Source: Nat Genet, 2009 Aug;41(8), p. 920-5.
EPub date: 2009 Jul 5.
PMID: 19578364
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A population-based study of Australian twins with melanoma suggests a strong genetic contribution to liability.
Authors: Shekar SN, Duffy DL, Youl P, Baxter AJ, Kvaskoff M, Whiteman DC, Green AC, Hughes MC, Hayward NK, Coates M, Martin NG
Source: J Invest Dermatol, 2009 Sep;129(9), p. 2211-9.
EPub date: 2009 Apr 9.
PMID: 19357710
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Polymorphisms in the syntaxin 17 gene are not associated with human cutaneous malignant melanoma.
Authors: Zhao ZZ, Duffy DL, Thomas SA, Martin NG, Hayward NK, Montgomery GW
Source: Melanoma Res, 2009 Apr;19(2), p. 80-6.
PMID: 19209086
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Histologic and epidemiologic correlates of P-MAPK, Brn-2, pRb, p53, and p16 immunostaining in cutaneous melanomas.
Authors: Richmond-Sinclair NM, Lee E, Cummings MC, Williamson R, Muller K, Green AC, Hayward NK, Whiteman DC
Source: Melanoma Res, 2008 Oct;18(5), p. 336-45.
PMID: 18781132
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A genome-wide linkage scan for age at menarche in three populations of European descent.
Authors: Anderson CA, Zhu G, Falchi M, van den Berg SM, Treloar SA, Spector TD, Martin NG, Boomsma DI, Visscher PM, Montgomery GW
Source: J Clin Endocrinol Metab, 2008 Oct;93(10), p. 3965-70.
EPub date: 2008 Jul 22.
PMID: 18647812
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Linkage and association analysis of spectrophotometrically quantified hair color in Australian adolescents: the effect of OCA2 and HERC2.
Authors: Shekar SN, Duffy DL, Frudakis T, Sturm RA, Zhao ZZ, Montgomery GW, Martin NG
Source: J Invest Dermatol, 2008 Dec;128(12), p. 2807-14.
EPub date: 2008 Jun 5.
PMID: 18528436
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Common sequence variants on 20q11.22 confer melanoma susceptibility.
Authors: Brown KM, Macgregor S, Montgomery GW, Craig DW, Zhao ZZ, Iyadurai K, Henders AK, Homer N, Campbell MJ, Stark M, Thomas S, Schmid H, Holland EA, Gillanders EM, Duffy DL, Maskiell JA, Jetann J, Ferguson M, Stephan DA, Cust AE, Whiteman D, Green A, Olsson H, Puig S, Ghiorzo P, Hansson J, Demenais F, Goldstein AM, Gruis NA, Elder DE, Bishop JN, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Martin NG, Trent JM, Mann GJ, Hayward NK
Source: Nat Genet, 2008 Jul;40(7), p. 838-40.
EPub date: 2008 May 18.
PMID: 18488026
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A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.
Authors: Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock S, Hunter DJ
Source: PLoS Genet, 2008 May 16;4(5), p. e1000074.
EPub date: 2008 May 16.
PMID: 18483556
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Spectrophotometric methods for quantifying pigmentation in human hair-influence of MC1R genotype and environment.
Authors: Shekar SN, Duffy DL, Frudakis T, Montgomery GW, James MR, Sturm RA, Martin NG
Source: Photochem Photobiol, 2008 May-Jun;84(3), p. 719-26.
PMID: 18435620
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The Queensland Study of Melanoma: environmental and genetic associations (Q-MEGA); study design, baseline characteristics, and repeatability of phenotype and sun exposure measures.
Authors: Baxter AJ, Hughes MC, Kvaskoff M, Siskind V, Shekar S, Aitken JF, Green AC, Duffy DL, Hayward NK, Martin NG, Whiteman DC
Source: Twin Res Hum Genet, 2008 Apr;11(2), p. 183-96.
PMID: 18361720
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Relative finger lengths, sex differences, and psychological traits.
Authors: Loehlin JC, Medland SE, Martin NG
Source: Arch Sex Behav, 2009 Apr;38(2), p. 298-305.
EPub date: 2008 Mar 14.
PMID: 18340520
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A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.
Authors: Sturm RA, Duffy DL, Zhao ZZ, Leite FP, Stark MS, Hayward NK, Martin NG, Montgomery GW
Source: Am J Hum Genet, 2008 Feb;82(2), p. 424-31.
EPub date: 2008 Jan 24.
PMID: 18252222
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Genetic dissection of myopia: evidence for linkage of ocular axial length to chromosome 5q.
Authors: Zhu G, Hewitt AW, Ruddle JB, Kearns LS, Brown SA, Mackinnon JR, Chen CY, Hammond CJ, Craig JE, Montgomery GW, Martin NG, Mackey DA
Source: Ophthalmology, 2008 Jun;115(6), p. 1053-1057.e2.
EPub date: 2007 Oct 26.
PMID: 17964656
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Estimation of variance components for age at menarche in twin families.
Authors: Anderson CA, Duffy DL, Martin NG, Visscher PM
Source: Behav Genet, 2007 Sep;37(5), p. 668-77.
EPub date: 2007 Aug 7.
PMID: 17680356
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