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Mendelian randomization can be applied to assess whether or not a causal relationship exists between vitamin D (X) and survival (Y). Arrows highlight proposed dependency between variables. The rs2282679 SNP (G) is considered a candidate for this assessment, as it is independent of lifestyle and other confounders. (b) shows a forest plot of the hazard ratios for overall survival in the 8 cohorts (separately and combined) based on the GC haplotype. Cox proportional hazards models were used to generate estimates (adjusted for age, sex, site and Breslow thickness).
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Survival from melanoma is influenced by several, well-established clinical and histopathological factors, e.g. age, Breslow thickness and microscopic ulceration. We (the Section of Epidemiology and Biostatistics, University of Leeds) have carried out research to better understand the biological basis for these observations. Preliminary results indi...
Citations
... This includes vitamin A and its derivatives, which can suppress the proliferation and invasion of melanoma cell lines by regulating the expression of EGFR and ICAM-1 [12]. Vitamins C and E can reduce the damage to the cell genome caused by UV by alleviating oxidative stress [12,13]. Although many in vitro studies have suggested that vitamin supplementation may be associated with a reduced risk of melanoma, epidemiological studies have not supported this evidence due to their controversial results [14][15][16]. ...
Melanoma, a prevalent and lethal form of skin cancer, remains a formidable challenge in terms of prevention and treatment. While significant progress has been made in understanding its pathogenesis and treatment, the quest for effective prevention strategies and therapeutic approaches remains ongoing. Considering the increased advancements in understanding the dynamic interplay between nutrients and melanoma, we aim to offer a refreshed perspective on nutrient-based approaches for melanoma prevention and adjunctive therapy. In contrast to other studies, we have innovatively provided a detailed exposition of the nutrients’ influences on melanoma prognosis and treatment. This review firstly examines various nutrients, including antioxidants (namely vitamins A, D, C, and E; selenium; and caffeine), polyunsaturated fatty acids, and flavonoids, for their effects and underlying mechanisms in reducing melanoma risk. Among these nutrients, caffeine shows the most promising potential, as it is supported by multiple cohort studies for its protective effect against melanoma. In contrast, there is a certain degree of inconsistency in the research of other nutrients, possibly due to inherent differences between animal studies and epidemiological research, as well as variations in the definition of nutrient intake. To comprehensively investigate the impact of nutrients on melanoma progression and therapeutic approaches, the following sections will explore how nutrients influence immune responses and other physiological processes. While there is robust support from cell and animal studies regarding the immunomodulatory attributes of vitamins D and zinc, the anti-angiogenic potential of polyphenols, and the cell growth-inhibitory effects of flavonoids, the limited availability of human-based research substantially constrains their practical relevance in clinical contexts. As for utilizing nutrients in adjuvant melanoma treatments, multiple approaches have garnered clinical research support, including the utilization of vitamin D to decrease the postoperative recurrence rates among melanoma patients and the adoption of a high-fiber diet to enhance the effectiveness of immunotherapy. In general, the effects of most nutrients on reducing the risk of melanoma are not entirely clear. However, several nutrients, including vitamin D and dietary fiber, have demonstrated their potential to improve the melanoma prognosis and enhance the treatment outcomes, making them particularly deserving of clinical attention. A personalized and interdisciplinary approach, involving dermatologists, oncologists, nutritionists, and researchers, holds the promise of optimizing melanoma treatment strategies.
... Changes in vitamin D3 levels are associated with several types of diseases, such as colon, breast, and skin cancer, and chronic inflammation 63 , although recent research also suggests vitamin D3 as a protective agent against many types of neoplasms 64 . The protective effect against cancer cells is associated with cell proliferation and differentiation, apoptosis, DNA repair, and inflammatory processes 65 . All diseases generated by changes in vitamin D3 levels have in common the interruption of endothelial stability and increased vascular leakage, often caused by injury or anatomical changes in the organ or tissue 66 . ...
Infertility is a worldwide concern, affecting one in six couples throughout their reproductive period. Therefore, enhancing the clinical tools available to identify the causes of infertility may save time, money, and emotional distress for the involved parties. This study aims to annotate potential biomarkers in follicular fluid that are negatively affecting pregnancy outcomes in women suffering infertility-related diseases such as endometriosis, tuboperitoneal factor, uterine factor, and unexplained infertility, using a metabolomics approach through high-resolution mass spectrometry. Follicular fluid samples collected from women who have the abovementioned diseases and managed to become pregnant after in vitro fertilization procedures [control group (CT)] were metabolically compared with those from women who suffer from the same diseases and could not get pregnant after the same treatment [infertile group (IF)]. Mass spectrometry analysis indicated 10 statistically relevant differential metabolites in the IF group, including phosphatidic acids, phosphatidylethanolamines, phosphatidylcholines, phosphatidylinositol, glucosylceramides, and 1-hydroxyvitamin D3 3- d -glucopyranoside. These metabolites are associated with cell signaling, cell proliferation, inflammation, oncogenesis, and apoptosis, and linked to infertility problems. Our results indicate that understanding the IF’s metabolic profile may result in a faster and more assertive female infertility diagnosis, lowering the costs, and increasing the probability of a positive pregnancy outcome.
... Thus, individuals who carry rs3769823-G may be predisposed to melanoma development via a role for this variant in inf luencing a switch from pro-apoptotic to anti-apoptotic functions of NF-κB. The potential role of vitamin D signalling in this context requires further exploration with an extensive literature linking low vitamin D levels to both risk of melanoma development and poor melanoma-associated outcomes (27). ...
A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher’s exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays (MPRA) provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the MC1R and TYR loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.
... Vitamin D has been found to have a significant role in melanoma survival as low levels of serum vitamin D are a negative prognostic indicator in melanoma (37,38). On the contrary, patients with high vitamin D levels have thinner melanoma tumours but also have higher number of naevi. ...
There is increasing evidence that the behaviour of naevi and melanoma is under significant genetic and/or epigenetic control. Melanoma tumours behaves similarly all over the world. Many genes have now been implicated in melanoma risk and naevi number. Embryogenesis has also been important in the discovery of links between several neurological diseases and melanoma susceptibility. Telomere biology, which regulates cell senescence, is increasingly relevant in melanoma. Melanoma is often found in the context of family cancer syndromes and the identification of these families is important as screening for cancer will save lives. Melanoma is also one of the most immunogenic cancer as the behaviour of naevi and melanoma differ in patients with vitiligo or eczema. The search for non-sun related melanoma risk factors should continue as it is likely to lead to important discoveries which will, in turn, have an impact on therapeutic targets for this tumour.
... 36,37 We have therefore expressed concern previously that there might be a narrow therapeutic window for a putative beneficial effect of vitamin D in melanoma 38 and the view that a conservative approach to supplementation should be adopted in order to avoid higher serum levels to avoid potential harm. 39 A transcriptomic study 40 reported evidence that higher vitamin D levels in melanoma patients were associated with less proliferative tumour phenotypes and a greater likelihood of a stronger immune gene signature. This is reassuring from a safety point of view, but it remains of concern that in the presence of loss of expression of VDR, higher vitamin D levels might be associated with adverse outcomes for poorer prognosis melanoma patients rather than having a protective effect. ...
Background:
Studies evaluating a relationship of vitamin D in patients with primary melanoma have consistently identified an inverse correlation with Breslow thickness, but an inconsistent impact on survival. Vitamin D in later stages of melanoma has been less studied.
Methods:
Vitamin D was measured in serum from 341 patients with resected stage IIB-IIIC melanoma recruited to the AVAST-M adjuvant melanoma randomised trial, collected prior to randomisation, then at 3 and 12 months. Vitamin D levels were compared with patient demographics, known melanoma prognostic factors, disease-free interval (DFI) and overall survival (OS).
Results:
A total of 73% patients had stage III melanoma, 32% were enroled (and therefore tested) >1 year after primary melanoma diagnosis. Median pre-randomisation vitamin D level was 56.5 (range 12.6-189.0 nmol/L). Vitamin D levels did not significantly vary over 12 months (p = 0.24). Individual pre-randomisation vitamin D levels did not differ significantly for Breslow thickness, tumour ulceration, or disease stage. Neither did pre-randomisation vitamin D predict for DFI (HR = 0.98 per 10 nmol/L increase; 95% confidence interval (CI) 0.93-1.04, p = 0.59) or OS (HR = 0.96 per 10 nmol/L increase, 95% CI 0.90-1.03, p = 0.31). For stage II patients, DFI improved with higher pre-randomisation vitamin D levels for those on bevacizumab (HR = 0.74 per 10 nmol nmol/L increase; 95% CI 0.56-0.97), but not for the observation arm (HR = 1.07 per 10 nmol/L increase; 95% CI 0.85-1.34).
Conclusions:
In this stage II/III melanoma cohort, vitamin D did not correlate with known prognostic markers, nor predict for DFI or OS, but there was some evidence of benefit for patients with stage II disease treated with bevacizumab.
... For example, a number of publications have associated low levels of vitamin D with cancer development. 12 13 The results highlighted improved survival of patients with higher vitamin D levels at the time of melanoma diagnosis, but the protective effect of vitamin D was reduced in patients with increased levels of vitamin A. As both vitamin D levels and melanomacausing DNA damage are associated with exposure to ultraviolet radiation, the link between increased vitamin D and reduced melanoma risk remains controversial. However, understanding the basic biological mechanisms relating vitamin D and vitamin A to melanoma development and progression might lead to the identification of disease-modifying biomarkers that may be potential prognostic identifiers or therapeutic targets. ...
... Meta-analyses have demonstrated a benefit of vitamin D supplementation on survival in cancer patients (Keum andGiovanucci 2014, Schotker et al. 2014;Hu et al 2017). In relation to melanoma, a few epidemiologic studies have investigated the relationship of serum vitamin D and disease specific outcomes (Bade et al., 2014;Fang et al., 2016;Gambichler et al., 2013;Newton-Bishop et al., 2009;Nurnberg et al., 2009;O'Shea et al., 2016; higher vitamin D levels have been associated with thinner tumors (Bade et al., 2014;Gambichler et al., 2013;Randerson-Moor et al., 2009), although this effects may also be due to greater surveillance. Higher vitamin D levels have been associated with longer overall and melanoma specific survival (Bade et al., 2014;Fang et al., 2016;Newton-Bishop et al., 2009;O'Shea et al., 2016). ...
... In relation to melanoma, a few epidemiologic studies have investigated the relationship of serum vitamin D and disease specific outcomes (Bade et al., 2014;Fang et al., 2016;Gambichler et al., 2013;Newton-Bishop et al., 2009;Nurnberg et al., 2009;O'Shea et al., 2016; higher vitamin D levels have been associated with thinner tumors (Bade et al., 2014;Gambichler et al., 2013;Randerson-Moor et al., 2009), although this effects may also be due to greater surveillance. Higher vitamin D levels have been associated with longer overall and melanoma specific survival (Bade et al., 2014;Fang et al., 2016;Newton-Bishop et al., 2009;O'Shea et al., 2016). ...
... The evidence on the relationship between the vitamin D pathway and outcomes in melanoma is growing Newton-Bishop et al., 2009;Newton-Bishop et al., 2015;Orlow et al., 2016;O'Shea et al., 2016;Sondak et al., 2016;Yin et al., 2016), although it is not always clear (Saiag et al., 2015). Fang et al. (2016) recently demonstrated that vitamin D levels were significantly associated with overall, disease-free, and melanoma-specific survival. ...
Evidence on the relationship between the vitamin D pathway and outcomes in melanoma is growing, although it is not always clear. We investigated the impact of measured levels of sun exposure at diagnosis on associations of vitamin D receptor gene (VDR) polymorphisms and melanoma-death in 3336 incident primary melanoma cases. Interactions between six SNPs and a common 3' end haplotype were significant (p<0.05). These SNPs, and a haplotype, had a statistically significant association with survival among subjects exposed to high UVB in multivariable regression models, and exerted their effect in the opposite direction among those with low UVB. SNPs rs1544410/BsmI and rs731236/TaqI remained significant after adjustment for multiple testing. These results suggest that the association between VDR and melanoma-specific survival is modified by sun exposure around diagnosis, and require validation in an independent study. Whether the observed effects are dependent or independent of vitamin D activation, remains to be determined. This article is protected by copyright. All rights reserved.
... 38 The initial report from the Leeds group described a prospective cohort study of 872 patients with a Breslow thickness greater than 0.75 mm. 39 Higher vitamin D levels at diagnosis were associated with a lower Breslow thickness (p = .002), were protective of risk of relapse (HR, 0.79; 95% CI, 0.6-0.96; ...
The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early-stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights.
... Furthermore, a recent study by Piotrowska et al. showed the antiproliferative effects of vitamin D analogs against human malignant melanoma cell lines (183). Vitamin D has been suggested to be associated with primary melanomas and could potentially influence the outcome of melanoma (184). Known melanoma-related signaling pathways have been shown to be regulated by vitamin D signaling, and many biological mechanisms of vitamin D3 action are directly associated with the vitamin D receptor (VDR) (185). ...
Background
We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.
Methods
We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.
Results
We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.
Conclusions
Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.
