Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk

Liu H., Wang L.-E., Liu Z., Chen W.V., Amos C.I., Lee J.E., Iles M.M., Law M.H., Barrett J.H., Montgomery G.W., Taylor J.C., Macgregor S., Cust A.E., Bishop J.A.N., Hayward N.K., Bishop D.T., Mann G.J., Affleck P. and Wei Q. (2013) Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk. Carcinogenesis, 34 4: 885-892. doi:10.1093/carcin/bgs407

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Author Liu H.
Wang L.-E.
Liu Z.
Chen W.V.
Amos C.I.
Lee J.E.
Iles M.M.
Law M.H.
Barrett J.H.
Montgomery G.W.
Taylor J.C.
Macgregor S.
Cust A.E.
Bishop J.A.N.
Hayward N.K.
Bishop D.T.
Mann G.J.
Affleck P.
Wei Q.
Title Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk
Journal name Carcinogenesis   Check publisher's open access policy
ISSN 0143-3334
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1093/carcin/bgs407
Open Access Status Not Open Access
Volume 34
Issue 4
Start page 885
End page 892
Total pages 8
Place of publication Oxford, England. U.K.
Publisher Oxford University Press
Language eng
Subject 1306 Cancer Research
Abstract 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.
Keyword Oncology
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID CA88363
R01 CA100264
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
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Created: Sun, 23 Feb 2014, 22:45:50 EST by Matthew Lamb on behalf of School of Medicine