Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk
| Autor: | Jennifer H. Barrett, GenoMEL Investigators, Grant W. Montgomery, Nicholas K. Hayward, Stuart MacGregor, D. Timothy Bishop, Li-E Wang, Qingyi Wei, Christopher I. Amos, Wei Chen, Hongliang Liu, Matthew Law, Paul Affleck, Jeffrey E. Lee, John C. Taylor, Graham J. Mann, Mark M. Iles, Q-Mega, Julia A. Newton Bishop, Amfs Investigators, Zhensheng Liu, Anne E. Cust |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Risk Cancer Research Skin Neoplasms Genotype MAP Kinase Signaling System MafF Transcription Factor Original Manuscript Single-nucleotide polymorphism Locus (genetics) Genome-wide association study Biology Bioinformatics Polymorphism Single Nucleotide Cell Line Group VI Phospholipases A2 03 medical and health sciences 0302 clinical medicine Humans SNP Genetic Predisposition to Disease RNA Messenger International HapMap Project Melanoma Genetic Association Studies Skin 030304 developmental biology Genetic association Genetics 0303 health sciences Nuclear Proteins General Medicine Odds ratio Middle Aged 3. Good health 030220 oncology & carcinogenesis Dual-Specificity Phosphatases Mitogen-Activated Protein Kinase Phosphatases Female Mitogen-Activated Protein Kinases Genome-Wide Association Study |
| Zdroj: | Carcinogenesis, 34(4), 885-892 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | 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 3ʹ 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. |
| Databáze: | OpenAIRE |
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