title: Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk.
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.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.forename: Li-E
authors.initials: LE
authors.lastname: Wang
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: Mark M
authors.initials: MM
authors.lastname: Iles
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Law
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cust
authors.forename: Julia A
authors.initials: JA
authors.lastname: Newton Bishop
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Paul
authors.initials: P
authors.lastname: Affleck
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D002460:Cell Line; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D054522:Group VI Phospholipases A2 / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051260:MafF Transcription Factor / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012306:Risk; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: C484147:MAFF protein, human; D051260:MafF Transcription Factor; D009687:Nuclear Proteins; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C498843:DUSP14 protein, human; D054637:Dual-Specificity Phosphatases