TY - JOUR
T1 - Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk
AU - Liu, Hongliang
AU - Wang, Li E.
AU - Liu, Zhensheng
AU - Chen, Wei V.
AU - Amos, Christopher I.
AU - Lee, Jeffrey E.
AU - Iles, Mark M.
AU - Law, Matthew H.
AU - Barrett, Jennifer H.
AU - Montgomery, Grant W.
AU - Taylor, John C.
AU - Macgregor, Stuart
AU - Cust, Anne E.
AU - Bishop, Julia A.Newton
AU - Hayward, Nicholas K.
AU - Bishop, D. Timothy
AU - Mann, Graham J.
AU - Affleck, Paul
AU - Wei, Qingyi
N1 - Funding Information:
Melanoma Research Alliance, the National Institutes of Health/ National Cancer Institute (CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449); the National Health and Medical Research Council of Australia (107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 496739, 552485 and 552498); the Cancer Councils NSW, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne), the Australian Cancer Research Foundation, the Wellcome Trust (WT084766/Z/08/Z) and donations from Neville and Shirley Hawkins. National Health and Medical Research Council of Australia Fellowships scheme (N.K.H. and G.W.M.). S.M. is the recipient of a Career Development Award from the National Health and Medical Research Council of Australia (496674 and 613705). AEC is supported by fellowships from the Cancer Institute NSW and the NHMRC. Cancer Australia grant (1011143 to M.H.L.). GenoMEL has received substantial funding from the European Commission under the Sixth Framework Programme (Contract no: LSHC-CT-2006–018702) from the National Cancer Institute of the US National Institutes of Health (CA83115) and from Cancer Research UK (C588/A4994, C588/A10589 and C8216/A6129).
PY - 2013/4
Y1 - 2013/4
N2 - Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P ≤ 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3' untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82-0.96, P = 0.003, false discovery rate = 0.056). Further genotype-phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.
AB - Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P ≤ 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3' untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82-0.96, P = 0.003, false discovery rate = 0.056). Further genotype-phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.
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U2 - 10.1093/carcin/bgs407
DO - 10.1093/carcin/bgs407
M3 - Article
C2 - 23291271
AN - SCOPUS:84875953413
SN - 0143-3334
VL - 34
SP - 885
EP - 892
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -