Polyunsaturated fatty acids and risk of melanoma: A Mendelian randomisation analysis

Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome‐wide association study (GWAS) meta‐analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta‐analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark “large” predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio [OR] = 1.03 (95% confidence interval [CI] = 0.96–1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis

Is there a causal relationship between vitamin D and melanoma risk? : A Mendelian randomization study.

BACKGROUND: Several pre-clinical studies have identified the anti-proliferative effects of 25-hydroxyvitamin D (25(OH) D; vitamin D). Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret due to the potential confounding from the dual role of UVR. OBJECTIVES: Our objective was to determine whether there is a causal association between genetically predicted 25(OH) D concentrations and melanoma using a Mendelian randomization (MR) approach. METHODS: We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12,874 cases and 23,203 controls. Five SNPs that are associated with 25(OH) D concentration rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 were selected as instrumental variables (IVs). Inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data. RESULTS: A 20 nmol/L decrease in 25(OH) D was not associated with melanoma risk (OR = 1.06, 95% CI = 0.94 - 1.19). Results from the UK Biobank were concordant with this, with meta-analysis of our and UK Biobank derived MR causal estimates showing no association (OR = 1.02, 95% CI = 0.92 - 1.13 for a 20nmol/L decrease). CONCLUSIONS: Our study results suggest that the genetically vitamin D levels may not be causally associated with the risk of melanoma. This article is protected by copyright. All rights reserved

Assessment of melanoma candidate genes in a meta‐analysis of 16 534 melanoma cases

Background: Numerous single nucleotide polymorphisms (SNPs) have been implicated with cutaneous melanoma (CM) Objective: The aim of our study was to establish novel susceptibility loci for CM by assessing candidate genes in a published meta‐analysis of 11 genome‐wide association studies (GWASs). Methods: 760 variants were retrieved from the MelGene database and tested for association in a meta‐analysis of 11 GWASs consisting of 12,874 CM cases and 23,303 controls of European ancestry. We calculated a false discovery rate and variants that surpassed this p‐value threshold were genotyped in three independent replication samples from UK, Greece and Cyprus. We excluded variants robustly associated with CM or in linkage disequilibrium with already known loci. The results from the GWASs and replication stages were synthesized in a meta‐analysis. Results: Based on our approach, the rs909253 polymorphism in the LTA gene (Lymphotoxin Alpha) was followed up for further consideration. The meta‐analysis of the 11 GWAS indicated a protective effect for the G allele on the risk of CM (OR: 0.921, p‐value: 2.7x10‐5). However, the estimates from the three replication samples were not statistically significant. The combined meta‐analysis of 3,660 CM cases and 350,915 cancer‐free controls provided a similar OR (0.935, p‐value: 1.95x10‐5); very large studies in the future will be required to determine if this SNP is a genuine melanoma risk SNP. Conclusion: By assessing over 16,000 CM cases, none of the published candidate genes tested for association with CM were significant in our study. Interest should be shifted to larger GWAS

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12,874 melanoma cases and 23,203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3,102 cases and 2,301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the Receiver Operator Characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC= 64.4%; 95% CI=63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR=1.35 (95% CI=1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year old Italian man ranged from 0.5% to 11.8% (RR=26.34), indicating good separation

A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure

Overlapping genetic architecture between Parkinson disease and melanoma

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.Hereditary cancer genetic

Overlapping genetic architecture between Parkinson disease and melanoma

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression