Melbourne School of Population and Global Health - Research Publications

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Author: CUST, ANNE × Author: Hopper, John × Author: Jenkins, Mark × Author: MASKIELL, JUDITH ×

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    Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3
    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-Scarra, G ; Hansson, J ; Demenais, F ; Landi, MT ; Debniak, 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, L-E ; 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 (NATURE PUBLISHING GROUP, 2011-11)
    We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.
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    A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma
    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, G ; 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 (NATURE PUBLISHING GROUP, 2011-12-01)
    So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.