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Pena-Chilet M.,Health Research Institute INCLIVA | Ibarrola-Villava M.,Health Research Institute INCLIVA | Martin-Gonzalez M.,Ramon y Cajal Hospital | Feito M.,Hospital Universitario La Paz | And 6 more authors.

Background: Solar radiation should be avoided in melanoma patients. Nevertheless, this is the main means by which the body produces vitamin D. Evidence suggests a protective role against cancer for vitamin D. Since vitamin D performs its function by binding the receptor encoded by the vitamin D-receptor gene (VDR), most studies have focused on polymorphisms (SNPs) within this gene. However, the gene encoding the vitamin D-binding protein (GC) appears in recent studies as a major player in the role of a serum vitamin D level regulator and in Cutaneous Melanoma (CM) predisposition. Methods: We performed a case-control study of 12 polymorphisms on GC and 9 on VDR among 530 cases and 314 controls from Spanish population. Results: We found association between SNP rs12512631, located 3′downstream of GC, and risk of CM that seems to fit a dominant model (OR 1.63 95%CI 1.23-2.17 p-value 7×10-4). This association remained Bonferroni's correction and after adjustment for potential confounders (p-value 3×10-3) and even after increasing the sample size to 1729 individuals (p-value 0.0129). Moreover, we confirmed evidence of an association between CM susceptibility and the linkage disequilibrium block marked by tag-SNP rs222016 (p-value 0.032). This block covers the GC intron 1 region, with probable regulatory functions. Conclusion: To our knowledge, this is the first vitamin D pathway-related polymorphism study in melanoma risk conducted in the Spanish population. Furthermore, we show an association between polymorphisms in GC and melanoma risk, confirming recent studies in different populations. © 2013 Peña-Chilet et al. Source

Maccioni L.,German Cancer Research Center | Rachakonda P.S.,German Cancer Research Center | Bermejo J.L.,University of Heidelberg | Planelles D.,Center for Blood Transfusion | And 6 more authors.
BMC Cancer

Background: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS).Methods: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region.Results: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A-allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54).Conclusions: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes. © 2013 Maccioni et al.; licensee BioMed Central Ltd. Source

MacCioni L.,German Cancer Research Center | Rachakonda P.S.,German Cancer Research Center | Scherer D.,National Center for Tumor Diseases | Bermejo J.L.,University of Heidelberg | And 7 more authors.
International Journal of Cancer

Agouti signaling protein (ASIP) locus on chromosome 20q11 is implicated, as shown by genome-wide association studies, in phenotype variation and melanoma risk. We genotyped 837 melanoma cases and 1,154 controls for 21 single nucleotide polymorphisms (SNPs) informative for 495 polymorphisms at the locus. Our data showed an increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03-1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. The main effect of rs4911414, as reported previously, was in tandem with a 10 kb adjacent polymorphism rs1015362; two constituted risk-associated haplotype/diplotype. Except for rs1015363, none of the 12 tagging SNPs, genotyped to cover 239.9 kb region with polymorphisms linked to rs4911414 and rs1015362, were associated with melanoma. Our data confirmed a previous association of melanoma risk (OR 1.82, 95% CI 1.37-2.41) with rs4911442, located in intron 5 of the nuclear receptor coactivator 6 (NCOA6) gene. The rs910871, one of the six variants, genotyped to cover NCOA6, showed an association with melanoma risk (OR 1.33, 95% CI 1.04-1.70). Both, rs4911442 and rs910871 were in moderate linkage with a, previously reported, risk-associated rs910873 polymorphism. A haplotype from the variants within NCOA6 showed an association with risk of melanoma (OR 1.49, 95% CI 1.17-1.88). Interaction between risk-associated polymorphisms and previously genotyped melanocortin receptor 1 (MC1R) variants, in our study, was not statistically significant. Nevertheless, the carriers of the variant alleles over the background of MC1R variants were at a higher risk than the carriers not enriched for MC1R variants. Our data confirmed the association of different variants at chromosome 20q11 with melanoma risk. What's new? People with freckles and moles tend to have a higher risk of skin cancer. Variation in the ASIP gene, which participates in pigment production, has been associated with melanoma risk in previous reports. In this study, Maccioni et al. compared genotypes of people with and without melanoma, looking for a genetic variant that associated with cancer risk. They found an increased risk of melanoma for carriers of a polymorphism upstream of ASIP, as well as a polymorphism within an intron region of a gene, NCOA6, which lies downstream of ASIP and encodes a protein that regulates transcription and may be involved in a tumor suppressor pathway. Copyright © 2012 UICC. Source

Iles M.M.,St Jamess Hospital | Law M.H.,Queensland Institute of Medical Research | Stacey S.N.,DeCODE Genetics Inc. | Han J.,Harvard University | And 101 more authors.
Nature Genetics

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10 -12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity. Source

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