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Slominski RM, Kim TK, Janjetovic Z, Brożyna AA, Podgorska E, Dixon KM, Mason RS, Tuckey RC, Sharma R, Crossman DK, Elmets C, Raman C, Jetten AM, Indra AK, Slominski AT. Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling. Cancers (Basel) 2024; 16:2262. [PMID: 38927967 PMCID: PMC11201527 DOI: 10.3390/cancers16122262] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/09/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.
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Affiliation(s)
- Radomir M. Slominski
- Department of Rheumatology and Clinical Immunology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Tae-Kang Kim
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Zorica Janjetovic
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Anna A. Brożyna
- Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland;
| | - Ewa Podgorska
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Katie M. Dixon
- School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia; (K.M.D.); (R.S.M.)
| | - Rebecca S. Mason
- School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia; (K.M.D.); (R.S.M.)
| | - Robert C. Tuckey
- School of Molecular Sciences, University of Western Australia, Perth, WA 6009, Australia;
| | - Rahul Sharma
- Department of Biomedical Informatics and Data Science, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - David K. Crossman
- Department of Genetics and Bioinformatics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Craig Elmets
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Chander Raman
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Anton M. Jetten
- Cell Biology Section, NIEHS—National Institutes of Health, Research Triangle Park, NC 27709, USA;
| | - Arup K. Indra
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Andrzej T. Slominski
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Pathology and Laboratory Medicine Service, Veteran Administration Medical Center, Birmingham, AL 35233, USA
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Bounas N, Seretis K. Vitamin D and Cutaneous Melanoma Risk: An Umbrella Review of Systematic Reviews and Meta-Analyses. Photobiomodul Photomed Laser Surg 2024; 42:249-266. [PMID: 38662504 DOI: 10.1089/photob.2023.0175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024] Open
Abstract
Background: Vitamin D (VitD) properties can impact cancer cells. Despite the documented link between VitD levels and prevalence of several cancer types, conflicting findings have been reported for cutaneous melanoma (CM). Objective: This overview aims to compile the evidence from existing systematic reviews and meta-analyses, emphasizing the relationships between VitD serum levels, intake, receptor (VDR) gene polymorphisms, and CM risk. Methods: A literature search in electronic databases was conducted, based on certain inclusion criteria. Results: Twenty-one studies were included. Conflicting evidence between high VitD serum levels, dietary/supplementary intake, and CM risk is highlighted. VDR polymorphisms may play a role in the intricate CM pathogenesis. Also, high serum levels of VitD are associated with improved CM prognosis. Conclusions: This overview showed that the impact of VitD on CM is not clear, and thus further research is suggested to explore its true effect size on CM risk.
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Affiliation(s)
- Nikolaos Bounas
- Department of Plastic Surgery, Medical School, University of Ioannina, Ioannina, Greece
| | - Konstantinos Seretis
- Department of Plastic Surgery, Medical School, University of Ioannina, Ioannina, Greece
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Farnoush N, Khosravi-Mashizi M, Rahmani A, Barahman M, Soleymani S, Asadian F, Shirinzadeh-Dastgiri A, Vakili-Ojarood M, HaghighiKian SM, Naseri A, Aghasipour M, Shiri A, Aghili K, Neamatzadeh H. Updated Meta-Analysis of VDR FokI and TaqI Variants and Their Association with Melanoma Risk. ACTA MEDICA (HRADEC KRALOVE) 2024; 67:113-124. [PMID: 40179841 DOI: 10.14712/18059694.2025.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
BACKGROUND Research suggests that melanoma patients with low vitamin D levels exhibit a higher risk of tumor ulceration and increased tumor mitotic rates. This has led to investigations into the vitamin D receptor (VDR) gene concerning its potential link to melanoma susceptibility. This meta-analysis aims to explore the association between VDR FokI and TaqI polymorphisms and melanoma risk, with an emphasis on the need for research in diverse populations to enhance our conclusions regarding interactions between skin phenotypes and VDR variations. METHODS A comprehensive literature search was conducted in databases, including PubMed, Scopus, and Web of Science, for studies linking VDR polymorphisms to melanoma risk, up to February 1, 2024. Keywords used included "Melanoma", "VDR", and various genetic terms. Quantitative synthesis was performed with Comprehensive Meta-Analysis (Version 4.0) and a significance threshold set at p < 0.05. RESULTS A total of twenty-one case-control studies involving 8,813 melanoma cases and 7,973 controls were included. Twelve studies on FokI had 4,642 cases and 4,534 controls, while nine TaqI studies included 4,171 cases and 3,439 controls. The results show a significant association between the VDR FokI polymorphism and increased melanoma risk across four genetic models (allele model: OR = 1.128, 95% CI 1.026-1.241; P = 0.013; homozygote model: OR = 1.166, 95% CI 1.020-1.332; P = 0.025; heterozygote model: OR = 1.255, 95% CI 1.046-1.507; P = 0.015; dominant model: OR = 1.243, 95% CI 1.052-1.470; P = 0.011). In contrast, the TaqI polymorphism showed no significant association with melanoma risk in the general population. CONCLUSIONS This meta-analysis suggests that the VDR FokI polymorphism is linked to an increased susceptibility to melanoma, while the TaqI variant does not show a significant association. Future research should explore the interactions between VDR polymorphisms, skin phenotypes, and melanoma risk in diverse populations, with larger and more varied studies needed to confirm these findings and enhance our understanding of genetic factors affecting melanoma susceptibility.
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Affiliation(s)
- Nazila Farnoush
- Department of General Surgery, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Khosravi-Mashizi
- Department of General Surgery, School of Medicine Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Rahmani
- Department of Plastic Surgery, Iranshahr University of Medical Sciences, Iranshahr, Iran.
| | - Maedeh Barahman
- Department of Radiation Oncology, Firoozgar Clinical Research Development Center (FCRDC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Soleymani
- Department of General Surgery, School of Medicine Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Asadian
- Department of Medical Laboratory Sciences, School of Paramedical Science, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Shirinzadeh-Dastgiri
- Department of Surgery, School of Medicine, Shohadaye Haft-e Tir Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Vakili-Ojarood
- Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Seyed Masoud HaghighiKian
- Department of General Surgery, School of Medicine Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhosein Naseri
- Department of Colorectal Surgery, Imam Reza Hospital, AJA University of Medical Sciences, Tehran, Iran
| | - Maryam Aghasipour
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Ohio, USA
| | - Amirmasoud Shiri
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kazem Aghili
- Department of Radiology, Shahid Rahnamoun Hospital, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Neamatzadeh
- Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Dobrică EC, Banciu ML, Kipkorir V, Khazeei Tabari MA, Cox MJ, Simhachalam Kutikuppala LV, Găman MA. Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis. World J Clin Cases 2022; 10:11214-11225. [PMID: 36387789 PMCID: PMC9649529 DOI: 10.12998/wjcc.v10.i31.11214] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted.
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Affiliation(s)
- Elena-Codruta Dobrică
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Madalina Laura Banciu
- Department of Dermatology, "Elias" University Emergency Hospital, Bucharest 011461, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy, University of Nairobi, College of Health Sciences, Nairobi 00100, Kenya
| | | | - Madeleine Jemima Cox
- University of New South Wales, University of New South Wales, Sydney 2052, Australia
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
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Gleba JJ, Kłopotowska D, Banach J, Turlej E, Mielko KA, Gębura K, Bogunia-Kubik K, Kutner A, Wietrzyk J. Polymorphism of VDR Gene and the Sensitivity of Human Leukemia and Lymphoma Cells to Active Forms of Vitamin D. Cancers (Basel) 2022; 14:387. [PMID: 35053549 PMCID: PMC8774213 DOI: 10.3390/cancers14020387] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/12/2022] [Accepted: 01/12/2022] [Indexed: 12/22/2022] Open
Abstract
The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the "bat" haplotype were observed only in the sensitive cells.
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Affiliation(s)
- Justyna Joanna Gleba
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Dagmara Kłopotowska
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Joanna Banach
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Eliza Turlej
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Norwida 27 B, 50-375 Wroclaw, Poland;
| | - Karolina Anna Mielko
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
- Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wroclaw University of Science and Technology, Norwida 4/6, 50-373 Wroclaw, Poland;
| | - Katarzyna Gębura
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (K.G.); (K.B.-K.)
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (K.G.); (K.B.-K.)
| | - Andrzej Kutner
- Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland;
| | - Joanna Wietrzyk
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
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Role of purinergic system and vitamin D in the anti-cancer immune response. Life Sci 2021; 287:120110. [PMID: 34743945 DOI: 10.1016/j.lfs.2021.120110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022]
Abstract
For several years, scientists have recognized that vitamin D plays an important role in mineral and bone homeostasis. It was mostly used to treat osteoporosis and rickets in the past decades. Vitamin D has also been discovered to be modulator of the immune system and may play a role in a variety of diseases, including autoimmune diseases, in recent years. Vitamin D interaction with the vitamin D receptor (VDR), which has transcriptional imparts and is displayed on a variety of cell types, including those of the immune system, appears to be accountable for the immune-modulating effects. The action of tumor cells and vitamin D were the first to be investigated, but the spotlight is now on immunologic and purinergic systems. We conducted a systematic search in Pub Med as well as Google scholar for studies written in English. Vitamin D, cancer, purinergic signaling, and immune response were among the search words. Vitamin D has the potential to be a useful coadjuvant in cancer therapy and the purinergic system may be a potential treatment target to cancer therapy, according to our findings.
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Gariazzo L, Gasparini G, Casabella A, Carmisciano L, Clapasson A, Murgioni F, Molfetta L, Cozzani E, Parodi A. Is ultraviolet radiation avoidance affecting bone health in melanoma patients? PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2021; 37:329-333. [PMID: 33432678 DOI: 10.1111/phpp.12657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/21/2020] [Accepted: 01/06/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Ultraviolet (UV) radiation has numerous beneficial effects on human health, including stimulating vitamin D and serotonin production and immuno-regulatory activities. Conversely, UV radiation is also classified as a group one carcinogen by the International Agency for Research on Cancer. PURPOSE To investigated the effects of UV radiation avoidance in melanoma patients in terms of vitamin D levels but also of bone mineral density and trabecular bone microarchitecture. METHODS We conducted an observational study investigating the effects of UV radiation avoidance in 31 melanoma patients in terms of vitamin D levels but also of bone mineral density and trabecular bone microarchitecture by using dual-energy X-ray absorptiometry scan. Data were compared with two control groups of healthy subjects, who were chronically exposed or not exposed to UV radiation during their lifetime. RESULTS Melanoma patients had on average slightly lower levels of vitamin D, without reaching statistical significance (P = .135). No significant difference was found across the three groups on T-scores of femoral neck (P = .544), of total hip (P = .617) and of lumbar spine P = .155). No significant difference was found on and trabecular bone score across exposure groups (P = .895). CONCLUSION UV radiation avoidance does not seem to significantly impact vitamin D levels nor bone health in melanoma patients. Thus, UV protective behavior is advisable for all melanoma patients.
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Affiliation(s)
- Lodovica Gariazzo
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Giulia Gasparini
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy.,Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Andrea Casabella
- University of Genoa, School of Medical and Pharmaceutical Sciences, Research Centre of Ostoeporosis and osteoarticular disease Di.M.I., Policlinic hospital San Martino, Genoa, Italy
| | - Luca Carmisciano
- Section of Biostatistics, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
| | - Andrea Clapasson
- Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Franca Murgioni
- Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Luigi Molfetta
- University of Genoa, School of Medical and Pharmaceutical Sciences, Research Centre of Ostoeporosis and osteoarticular disease Di.M.I., Policlinic hospital San Martino, Genoa, Italy
| | - Emanuele Cozzani
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | - Aurora Parodi
- Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.,Dermatology Unit, Ospedale Policlinico San Martino IRCCS, Genoa, Italy
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Mahamat-Saleh Y, Aune D, Schlesinger S. 25-Hydroxyvitamin D status, vitamin D intake, and skin cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Sci Rep 2020; 10:13151. [PMID: 32753685 PMCID: PMC7403339 DOI: 10.1038/s41598-020-70078-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 06/14/2020] [Indexed: 02/06/2023] Open
Abstract
Sun exposure is a major environmental risk factor for skin cancers and is also an important source of vitamin D. However, while experimental evidence suggests that vitamin D may have a protective effect on skin cancer risk, epidemiologic studies investigating the influence of 25-hydroxyvitamin D (25(OH)D) level and/or vitamin D intake on skin cancer risk are conflicting. A systematic review and dose–response meta-analyses of prospective studies was conducted to clarify these associations. Relevant studies were identified by searching the PubMed database up to 30th August 2019. Random effects dose–response meta-analyses were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Overall, thirteen prospective studies were included. Circulating level of 25(OH)D was associated with higher risks of melanoma (SRR (95% CI) per 30 nmol = 1.42 (1.17–1.72)) and keratinocyte cancer (KC) (SRR (95% CI) per 30 nmol/L = 1.30 (1.13–1.49)). The SRR (95% CI) per 30 nmol/L increase in 25(OH) D level was 1.41 (1.19–1.67), and 1.57 (0.64–3.86), for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), respectively. However, while we found that vitamin D intake (from diet, supplemental and total) was not associated with risks of melanoma and SCC, vitamin D intake was associated with slightly increased BCC risk, albeit with no heterogeneity across skin cancer type. This meta-analysis suggests positive associations between circulating 25(OH)D level and risk of melanoma and KC, however, this finding is most likely confounded by sun exposure. We found no associations between vitamin D intake skin cancers, except positive associations with BCC risk.
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Affiliation(s)
- Yahya Mahamat-Saleh
- CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris Saclay, 94 805, Villejuif, France. .,Inserm U1018, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France.
| | - Dagfinn Aune
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.,Department of Nutrition, Bjørknes University College, Oslo, Norway.,Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Ullevål, Oslo, Norway
| | - Sabrina Schlesinger
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research At Heinrich Heine University, Düsseldorf, Germany
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Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev 2019; 40:1109-1151. [PMID: 30321335 PMCID: PMC6626501 DOI: 10.1210/er.2018-00126] [Citation(s) in RCA: 648] [Impact Index Per Article: 108.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
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Affiliation(s)
- Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Daniel Bikle
- Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California
| | - John H White
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Bess Dawson-Hughes
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Paul Lips
- Department of Internal Medicine, Endocrine Section, VU University Medical Center, HV Amsterdam, Netherlands
| | - Craig F Munns
- Children’s Hospital at Westmead, Sydney, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Marise Lazaretti-Castro
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Andrea Giustina
- Chair of Endocrinology, Vita-Salute San Raffaele University, Milan, Italy
| | - John Bilezikian
- Department of Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York
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Vasilovici AF, Grigore LE, Ungureanu L, Fechete O, Candrea E, Trifa AP, Vișan S, Șenilă S, Cosgarea R. Vitamin D receptor polymorphisms and melanoma. Oncol Lett 2018; 17:4162-4169. [PMID: 30944611 PMCID: PMC6444280 DOI: 10.3892/ol.2018.9733] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Melanoma represents the most aggressive skin cancer, with an unpredictable and often treatment resistant behavior. The etiology of melanoma is multifactorial and includes both environmental and genetic factors. Recent evidence indicates that vitamin D has a role in the development and progression of melanoma. The biologically active form of vitamin D/1,25-dihydroxyvitamin D3 acts by binding to a intranuclear receptor; vitamin D receptor (VDR). Single nucleotide polymorphisms (SNPs) in the vitamin D receptor gene may alter the expression or the function of the VDR protein leading to various diseases, including melanoma. More than 600 SNPs have been identified in the VDR gene, but only a few have been analyzed in relation to melanoma risk: FokI, TaqI, BsmI, ApaI, Cdx2, EcoRV, and BglI. Individual studies carried on small cohorts of patients reported controversial results. In an attempt to clarify the available data in the literature on this subject, we elaborated a systematic review in which we analyzed the relationship between VDR gene polymorphisms and melanoma risk and progression. We concluded that vitamin D pathway is important for the pathogenesis and the progression of cutaneous melanoma, illustrating the gene-environment interactions, but well-designed prospective studies that include data on both genotypes and phenotypes of vitamin D metabolism are essential in order to understand the mechanisms underlying the association between vitamin D and melanoma.
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Affiliation(s)
- Alina F Vasilovici
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Lavinia Elena Grigore
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania.,Department of Dermatology, Municipal Clinical Hospital, 400139 Cluj-Napoca, Romania
| | - Loredana Ungureanu
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Oana Fechete
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Elisabeta Candrea
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Adrian P Trifa
- Department of Medical Genetics, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania.,Department of Genetics, The Oncology Institute 'Prof Dr. Ion Chiricuta', 400015 Cluj-Napoca, Romania.,Department of Genetics, Center for Advanced Medical and Pharmaceutical Research, University of Medicine and Pharmacy, 540142 Tîrgu-Mureș, Romania
| | - Simona Vișan
- Department of Genetics, The Oncology Institute 'Prof Dr. Ion Chiricuta', 400015 Cluj-Napoca, Romania
| | - Simona Șenilă
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Rodica Cosgarea
- Department of Dermatology, 'Iuliu Hațieganu' University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
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Morgese F, Soldato D, Pagliaretta S, Giampieri R, Brancorsini D, Torniai M, Rinaldi S, Savini A, Onofri A, Scarpelli M, Berardi R. Impact of phosphoinositide-3-kinase and vitamin D3 nuclear receptor single-nucleotide polymorphisms on the outcome of malignant melanoma patients. Oncotarget 2017; 8:75914-75923. [PMID: 29100280 PMCID: PMC5652674 DOI: 10.18632/oncotarget.18304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 04/27/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome. MATERIALS AND METHODS Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays. We selected polymorphisms of the regulatory and catalytic subunit of PI3K (PIK3R1 and PIK3CA genes, respectively), analyzing rs2699887C>T of PIK3CA and rs3730089G>A of PIK3R1 SNPs. Furthermore we considered the following VDR SNPs: rs2228570A>G (Fok1), rs731236A>G (Taq1) and rs1544410C>T (Bsm1).Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and with Mantel-Haenszel log-rank test. RESULTS The statistical analysis for Fok1 of VDR showed a significant difference in PFS after the first line therapy (median PFS= 21.2 months in the homozygous recessive genotype group vs. 3.3 months of homozygous dominant and heterozygous ones, p= 0.03). In particular, in homozygous recessive patients for Fok1 SNPs of VDR a high rate of histological regression and BRAF (B- Rapidly Accelerated Fibrosarcoma gene) mutation were observed. Furthermore, more efficacy of BRAF +/- MEK (MAPK-ERK-Kinase) inhibitors therapies in homozygous recessive patients vs. homozygous dominant and heterozygous ones was shown. CONCLUSIONS Our study showed a significant correlation between homozygous recessive genotype of Fok1 SNPs of VDR gene and an increased PFS in patients who underwent a first line therapy with BRAF inhibitors.
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Affiliation(s)
- Francesca Morgese
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Davide Soldato
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Silvia Pagliaretta
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Riccardo Giampieri
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Donatella Brancorsini
- Section of Pathological Anatomy and Histopathology, Deparment of Neuroscience, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Mariangela Torniai
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Silvia Rinaldi
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Agnese Savini
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Azzurra Onofri
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Marina Scarpelli
- Section of Pathological Anatomy and Histopathology, Deparment of Neuroscience, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
| | - Rossana Berardi
- Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I°-G.M. Lancisi-G. Salesi”, Ancona, Italy
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12
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Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. J Transl Med 2017; 97:706-724. [PMID: 28218743 PMCID: PMC5446295 DOI: 10.1038/labinvest.2017.3] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 12/19/2022] Open
Abstract
Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.
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13
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Vitamin D receptor immunohistochemistry variability in sun-exposed and non-sun-exposed melanomas. Melanoma Res 2017; 27:17-23. [DOI: 10.1097/cmr.0000000000000311] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Reichrath J, Zouboulis CC, Vogt T, Holick MF. Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook. Rev Endocr Metab Disord 2016; 17:405-417. [PMID: 27447175 DOI: 10.1007/s11154-016-9353-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Vitamin D represents one of the major driving factors for the development of life on earth and for human evolution. While up to 10-20 % of the human organism's requirements in vitamin D can be obtained by the diet (under most living conditions in the USA and Europe), approximately 90 % of all needed vitamin D has to be photosynthesized in the skin through the action of the sun (ultraviolet-B (UV-B)). The skin represents a key organ of the human body's vitamin D endocrine system (VDES), being both the site of vitamin D synthesis and a target tissue for biologically active vitamin D metabolites. It was shown that human keratinocytes possess the enzymatic machinery (CYP27B1) for the synthesis of the biologically most active natural vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), representing an autonomous vitamin D3 pathway. Cutaneous production of 1,25(OH)2D3 may exert intracrine, autocrine, and paracrine effects on keratinocytes and on neighboring cells. Many skin cells (including keratinocytes, sebocytes, fibroblasts, melanocytes, and skin immune cells) express the vitamin D receptor (VDR), an absolute pre-requisite for the mediation of genomic effects of 1,25(OH)2D3 and analogs. VDR belongs to the superfamily of trans-acting transcriptional regulatory factors, which includes the steroid and thyroid hormone receptors as well as the retinoid X receptors (RXR) and retinoic acid receptors (RAR). Numerous studies, including cDNA microarray analyses of messenger RNAs (mRNAs), indicate that as many as 500-1000 genes may be regulated by VDR ligands that control various cellular functions including growth, differentiation, and apoptosis. The observation that 1,25(OH)2D3 is extremely effective in inducing the terminal differentiation and in inhibiting the proliferation of cultured human keratinocytes has resulted in the use of vitamin D analogs for the treatment of psoriasis. This review gives an historical view and summarizes our present knowledge about the relevance of the VDES for the management of inflammatory and malignant skin diseases.
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Affiliation(s)
- Jörg Reichrath
- Center for Clinical and Experimental Photo-Dermatology and Department of Dermatology, The Saarland University Hospital, Kirrbergerstr, 66421, Homburg, Germany.
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany
| | - Thomas Vogt
- Center for Clinical and Experimental Photo-Dermatology and Department of Dermatology, The Saarland University Hospital, Kirrbergerstr, 66421, Homburg, Germany
| | - Michael F Holick
- Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University Medical Center, 85 E Newton St M-1013, Boston, MA, 02118, USA
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Tagliabue E, Raimondi S, Gandini S. Vitamin D, Cancer Risk, and Mortality. ADVANCES IN FOOD AND NUTRITION RESEARCH 2015; 75:1-52. [PMID: 26319903 DOI: 10.1016/bs.afnr.2015.06.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types by influencing cell differentiation and decreasing cell proliferation, growth, invasion, angiogenesis, and metastasis. Several meta-analyses showed that low serum levels of 25(OH)D was associated with colorectal cancer and overall mortality, while the association with cancer mortality was less consistent. VDR is a crucial mediator for the cellular effects of vitamin D and conflicting data have been reported for most malignancies. Beyond VDR, the biological effects of vitamin D are mediated by the vitamin D-binding protein. The GC (group-specific component) gene, encoding DBP, is highly polymorphic and several polymorphisms were investigated in association with cancer development with controversial results. Vitamin D supplementation was found to be associated with a reduced risk of overall mortality, reviewing all published trials on healthy subjects, whereas the evidence of an effect on cancer risk and mortality is less clear. Furthermore, long-term health effects of high doses of vitamin D, extended duration of supplementation, and the association with different baseline vitamin D levels remain to be investigated. In summary, epidemiological and preclinical studies support the development of vitamin D as preventative and therapeutic anticancer agents, with significant associations especially found for low vitamin D status with overall mortality and cancer outcome, more than cancer incidence. However, a definitive conclusion cannot be drawn and only large randomized clinical trials, both in healthy subjects and in cancer patients, will allow to draw definitive conclusions on the effect of vitamin D supplementation on cancer risk, prognosis, and mortality.
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Affiliation(s)
- Elena Tagliabue
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Sara Raimondi
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Sara Gandini
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
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16
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Wyatt C, Lucas RM, Hurst C, Kimlin MG. Vitamin D deficiency at melanoma diagnosis is associated with higher Breslow thickness. PLoS One 2015; 10:e0126394. [PMID: 25970336 PMCID: PMC4430535 DOI: 10.1371/journal.pone.0126394] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 04/01/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Epidemiological evidence shows that people with thicker, or higher stage, melanomas have lower vitamin D status compared to those with thinner tumours. Evidence from experimental studies is inconsistent, but some suggest that administration of vitamin D metabolites can decrease tumour aggressiveness. OBJECTIVES Determine the relationship between vitamin D status at diagnosis and melanoma thickness (as an indicator of prognosis), in a subtropical setting with high melanoma incidence. METHODS We recruited 100 melanoma patients in Brisbane, Australia within days of their diagnosis. Data on factors previously associated with melanoma risk or prognosis were collected by questionnaire and physical examination. Serum for 25-hydroxyvitamin D3 [25(OH)D] levels was collected prior to wider excision biopsy; histological indicators of prognosis were obtained from pathology reports. We used multivariable logistic regression models to analyse the association between Breslow thickness (≥0.75 mm compared to <0.75 mm), Clark level (2-5 compared to 1) and presence of mitoses, and vitamin D status. RESULTS Serum 25(OH)D <50 nmol/L (versus ≥50 nmol/L) was associated with a nearly four-fold increase in risk of having a thicker tumour (Adjusted OR = 3.82, 95% CI: 1.03, 14.14; p = 0.04, adjusted for age, sex, skin phototype, body mass index and season at diagnosis). There was no significant association with Clark level or presence of mitosis. Serum 25(OH)D levels in the highest quartile (≥69.8 nmol/L) were not associated with a more favourable prognosis. CONCLUSIONS Vitamin D deficiency at the time of melanoma diagnosis is associated with thicker tumours that are likely to have a poorer prognosis. Ensuring vitamin D levels of 50 nmol/L or higher in this population could potentially result in 18% of melanomas having Breslow thickness of <0.75 mm rather than ≥0.75 mm.
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Affiliation(s)
- Candy Wyatt
- AusSun Research Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- * E-mail:
| | - Robyn M. Lucas
- National Centre for Epidemiology and Population Health, The Australian National University, Canberra, Australia
- Telethon Kids Institute, University of Western Australia, Perth, Australia
| | - Cameron Hurst
- Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand
| | - Michael G. Kimlin
- AusSun Research Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
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Burns EM, Elmets CA, Yusuf N. Vitamin D and skin cancer. Photochem Photobiol 2014; 91:201-9. [PMID: 25378147 DOI: 10.1111/php.12382] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/20/2014] [Indexed: 12/14/2022]
Abstract
Vitamin D signaling plays a key role in many important processes, including cellular proliferation, differentiation and apoptosis, immune regulation, hormone secretion and skeletal health. Furthermore, vitamin D production and supplementation have been shown to exert protective effects via an unknown signaling mechanism involving the vitamin D receptor (VDR) in several diseases and cancer types, including skin cancer. With over 3.5 million new diagnoses in 2 million patients annually, skin cancer is the most common cancer type in the United States. While ultraviolet B (UVB) radiation is the main etiologic factor for nonmelanoma skin cancer (NMSC), UVB also induces cutaneous vitamin D production. This paradox has been the subject of contradictory findings in the literature in regards to amount of sun exposure necessary for appropriate vitamin D production, as well as any beneficial or detrimental effects of vitamin D supplementation for disease prevention. Further clinical and epidemiological studies are necessary to elucidate the role of vitamin D in skin carcinogenesis.
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Affiliation(s)
- Erin M Burns
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL
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18
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Murzaku EC, Bronsnick T, Rao BK. Diet in dermatology: Part II. Melanoma, chronic urticaria, and psoriasis. J Am Acad Dermatol 2014; 71:1053.e1-1053.e16. [PMID: 25454037 DOI: 10.1016/j.jaad.2014.06.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 06/04/2014] [Accepted: 06/09/2014] [Indexed: 02/07/2023]
Abstract
The roles of dietary factors in aggravating, preventing, or treating skin diseases are common questions encountered in dermatology practice. Part II of this two-part series reviews dietary modifications that can potentially be utilized in the management of melanoma, chronic urticaria, and psoriasis patients. Specifically, we examine the effect of alcohol consumption and supplementation with vitamins D and E, polyunsaturated fatty acids, selenium, green tea, resveratrol, and lycopene on melanoma risk. The relationships between chronic urticaria symptoms and dietary pseudoallergens, gluten, and vitamin D are analyzed. We explore weight loss, reduced alcohol consumption, and gluten avoidance as means of reducing psoriasis-associated morbidity, as well as the possible utility of supplementation with polyunsaturated fatty acids, folic acid, vitamin D, and antioxidants. With proper knowledge of the role of diet in these cutaneous disease processes, dermatologists can better answer patient inquiries and consider implementation of dietary modifications as adjuncts to other treatments and preventative measures.
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Affiliation(s)
- Era Caterina Murzaku
- Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Tara Bronsnick
- Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
| | - Babar K Rao
- Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
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Denzer N, Vogt T, Reichrath J. Vitamin D receptor (VDR) polymorphisms and skin cancer. DERMATO-ENDOCRINOLOGY 2014. [DOI: 10.4161/derm.16519] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Kosiniak-Kamysz A, Marczakiewicz-Lustig A, Marcińska M, Skowron M, Wojas-Pelc A, Pośpiech E, Branicki W. Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects. Melanoma Res 2014; 24:388-96. [PMID: 24926819 DOI: 10.1097/cmr.0000000000000095] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cutaneous malignant melanoma (CMM) is a malicious human skin cancer that primarily affects individuals with light pigmentation and heavy sun exposure, but also has a known familial association. Multiple genes and polymorphisms have been reported as low-penetrance susceptibility loci for CMM. Here, we examined 33 candidate polymorphisms located in 11 pigmentation genes and the vitamin D receptor gene (VDR) in a population of 130 cutaneous melanoma patients and 707 healthy controls. The genotypes obtained were evaluated for main association effects and potential gene-gene interactions. MC1R, TYR, VDR and SLC45A2 genes were found to be associated with CMM in our population. The results obtained for major function MC1R mutations were the most significant [with odds ratio (OR)=1.787, confidence interval (CI)=1.320-2.419 and P=1.715(-4)], followed by TYR (rs1393350) (with OR=1.569, CI=1.162-2.118, P=0.003), VDR (GCCC haplotype in rs2238136-rs4516035-rs7139166-rs11568820 block) (with OR=5.653, CI=1.794-17.811, P=0.003) and SLC45A2 (rs16891982) (with OR=0.238, CI=0.057-0.987, P=0.048). The study also detected significant intermolecular epistatic effects between MC1R and TYR, SLC45A2 and VDR, HERC2 and VDR, OCA2 and TPCN2, as well as intramolecular interactions between variants within the genes MC1R and VDR. In the final multivariate logistic regression model for CMM development, only the gene-gene interactions discovered remained significant, showing that epistasis may be an important factor in the risk of melanoma.
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Affiliation(s)
- Agnieszka Kosiniak-Kamysz
- aDepartment of Dermatology, Collegium Medicum of the Jagiellonian University bDepartment of Analytical Biochemistry, Jagiellonian University Medical College cDepartment of Genetics and Evolution, Institute of Zoology, Jagiellonian University dSection of Forensic Genetics, Institute of Forensic Research, Kraków, Poland
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21
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McNally JD, Sampson M, Matheson LA, Hutton B, Little J. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis. Pediatr Pulmonol 2014; 49:790-9. [PMID: 24019226 DOI: 10.1002/ppul.22877] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 06/29/2013] [Indexed: 12/30/2022]
Abstract
BACKGROUND A number of small studies have suggested a relationship between vitamin D status and severe acute lower respiratory tract infection (ALRI), including RSV-bronchiolitis. The objective of this study was to evaluate the relationship between vitamin D receptor (VDR) polymorphism and severe RSV-bronchiolitis through a systemic literature review and meta-analysis. METHODS A comprehensive electronic literature search was conducted to identify all studies published before January 2013. Two reviewers independently screened all abstracts, followed by the full text of potential articles to evaluate eligibility. Study methodological quality was evaluated using the Newcastle Ottawa scale and individual component analysis. Meta-analysis evaluated associations at the allele and genotype levels. RESULTS Of 803 studies identified from our literature search, three met eligibility criteria. Two VDR polymorphisms were included in more than one study: TaqI (rs731236) and FokI (rs2228570). All three reported a positive relationship between the FokI minor allele and disease with random effects meta-analyses demonstrating a statistically significant relationship (OR 1.52, CI: 1.12, 2.05). Genotype analysis was highly suggestive of a dominant or incomplete dominance model with combined odds ratios for fF (OR 1.73, CI: 0.92-3.36) and ff (OR 2.24, CI: 0.98-5.14) compared to the FF genotype. No association between TaqI and severe RSV-bronchiolitis was evident at the allele or genotype level. CONCLUSIONS Available literature supports an association between the FokI polymorphism and severe RSV disease. Determination of VDR receptor polymorphism status could help predict high-risk infants who might benefit from preventive measures.
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Affiliation(s)
- J Dayre McNally
- Department of Pediatrics, Faculty of Medicine, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, Canada; Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Canada
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Gnagnarella P, Pasquali E, Serrano D, Raimondi S, Disalvatore D, Gandini S. Vitamin D receptor polymorphism FokI and cancer risk: a comprehensive meta-analysis. Carcinogenesis 2014; 35:1913-9. [PMID: 25053622 DOI: 10.1093/carcin/bgu150] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Numerous studies investigated the associations of VDR polymorphisms with various types of cancer, suggesting an influence on cancer risk. FokI is one of the most frequently analysed polymorphisms but the results from single studies are contradictory. We performed a meta-analysis looking at the association between the FokI and all cancer sites and investigating sources of heterogeneity. We identified 77 independent studies up to April 2014. We presented the summary odds ratios (SORs) by cancer sites, ethnicity and study features. We found a significant association between FokI and ovarian cancer for ff genotype versus FF with no heterogeneity: SOR = 1.20 (95% CI: 1.02-1.41, I (2) = 0%). Moreover, we found a significant increased risk of any cancer: SOR = 1.08 (95% CI: 1.01-1.16, I (2) = 58%). A significant increased risk of any cancer is confirmed among Caucasian, among studies in Hardy-Weinberg equilibrium and nested case-control studies. Furthermore, among studies in Hardy-Weinberg equilibrium, skin cancer was found significantly associated with FokI: SOR = 1.24 (95% CI: 1.01-1.54; I (2) = 24%) for ff versus FF. The estimated number of cases attributable to ff genotype is 4221 for ovarian cancer and 52858 for skin cancer worldwide each year. No indication for publication bias was found for any cancer site. In conclusion, we found an overall significant association of FokI polymorphism with any cancer, with differential effect by ethnicity. In particular, the summary estimates indicate an increase risk for ovarian and skin cancer for ff versus FF. However, other factors may act modifying the association, and further studies are needed to clarify the impact on cancer risk.
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Affiliation(s)
- Patrizia Gnagnarella
- Division of Epidemiology and Biostatistics and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
| | - Elena Pasquali
- Division of Epidemiology and Biostatistics and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
| | - Davide Serrano
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
| | - Sara Raimondi
- Division of Epidemiology and Biostatistics and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
| | - Davide Disalvatore
- Division of Epidemiology and Biostatistics and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
| | - Sara Gandini
- Division of Epidemiology and Biostatistics and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan 20141, Italy
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Polymorphisms in the vitamin D receptor (VDR) genes and skin cancer risk in European population: a meta-analysis. Arch Dermatol Res 2014; 306:545-53. [DOI: 10.1007/s00403-014-1464-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 03/25/2014] [Accepted: 04/02/2014] [Indexed: 10/25/2022]
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Xu Y, He B, Pan Y, Deng Q, Sun H, Li R, Gao T, Song G, Wang S. Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Tumour Biol 2014. [PMID: 24408013 DOI: 10.1007/s13277-013-1544- y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this meta-analysis was conducted to clarify the association between VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) and cancer risk. One hundred twenty-six studies were enrolled through PubMed. For VDR BsmI polymorphism, significantly increased cancer risks were observed in the overall analysis. In the further stratified analysis, increased risks were observed in colorectal and skin cancer, especially in Caucasian population. However, no significant associations were observed in other VDR polymorphisms in the overall analysis. In the further subgroup analysis, increased risks were found in oral, breast, and basal cell cancer while decreased risk was found in prostate cancer in t allele carriers of TaqI polymorphism. For VDR FokI polymorphism, increased risks were found in ovarian and skin cancer while decreased risk in glioma in f allele carriers. For VDR ApaI polymorphism, increased risk was observed in basal cell cancer, especially in Asian population in a allele carriers. In conclusion, these results indicated that b allele of BamI polymorphism was a risk factor for cancer susceptibility. Meanwhile, t allele of TaqI polymorphism was a risk factor for oral, breast, and basal cell cancer and a protective factor for prostate cancer. Moreover, f allele of FokI polymorphism was a risk factor for ovarian and skin cancer and a protective factor for glioma. Finally, a allele of ApaI polymorphism was a risk factor for basal cell cancer in Asian population.
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Affiliation(s)
- Yeqiong Xu
- Central Laboratory of Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
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Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Tumour Biol 2014; 35:4153-69. [PMID: 24408013 DOI: 10.1007/s13277-013-1544-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 12/11/2013] [Indexed: 12/31/2022] Open
Abstract
The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this meta-analysis was conducted to clarify the association between VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) and cancer risk. One hundred twenty-six studies were enrolled through PubMed. For VDR BsmI polymorphism, significantly increased cancer risks were observed in the overall analysis. In the further stratified analysis, increased risks were observed in colorectal and skin cancer, especially in Caucasian population. However, no significant associations were observed in other VDR polymorphisms in the overall analysis. In the further subgroup analysis, increased risks were found in oral, breast, and basal cell cancer while decreased risk was found in prostate cancer in t allele carriers of TaqI polymorphism. For VDR FokI polymorphism, increased risks were found in ovarian and skin cancer while decreased risk in glioma in f allele carriers. For VDR ApaI polymorphism, increased risk was observed in basal cell cancer, especially in Asian population in a allele carriers. In conclusion, these results indicated that b allele of BamI polymorphism was a risk factor for cancer susceptibility. Meanwhile, t allele of TaqI polymorphism was a risk factor for oral, breast, and basal cell cancer and a protective factor for prostate cancer. Moreover, f allele of FokI polymorphism was a risk factor for ovarian and skin cancer and a protective factor for glioma. Finally, a allele of ApaI polymorphism was a risk factor for basal cell cancer in Asian population.
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27
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Liu Y, Li C, Chen P, Li X, Li M, Guo H, Li J, Chu R, Wang H. Polymorphisms in the vitamin D Receptor (VDR) and the risk of ovarian cancer: a meta-analysis. PLoS One 2013; 8:e66716. [PMID: 23826116 PMCID: PMC3691226 DOI: 10.1371/journal.pone.0066716] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 05/09/2013] [Indexed: 12/31/2022] Open
Abstract
The vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Various epidemiological studies have investigated the associations of VDR gene polymorphisms with ovarian cancer; however, the results have been inconclusive. In the current study, we evaluated, in a meta-analysis, the association of five common single nucleotide polymorphisms (SNPs) in the VDR gene (ApaI, BsmI, Cdx-2, FokI, and TaqI) with the risk of ovarian cancer. Six eligible studies, with a total of 4,107 cases and 6,661 controls, which evaluated the association of these variants and ovarian cancer risk, were identified from the MEDLINE and PubMed databases. The meta-analysis indicated that FokI was associated with an increased ovarian cancer risk, with a pooled odds ratio (OR) of 1.10 [95% confidence intervals (95% CI) = 1.00-1.20] for CT heterozygotes and 1.16 (95% CI = 1.02-1.30) for TT homozygotes relative to common CC carriers. Carriers of the T allele (also known as the f allele) showed an 11% (pooled OR = 1.11, 95% CI = 1.02-1.21; TT/CT vs. CC) increased risk of ovarian cancer relative to CC carriers. For FokI, no significant heterogeneity between the studies was found (I(2) = 0%, P = 0.62 for the Q test). There was no statistically significant association between the other four variants (ApaI, BsmI, Cdx-2 and TaqI) and risk of ovarian cancer. These data indicate that the polymorphism FokI on the VDR is a susceptibility factor for ovarian cancer. Nevertheless, more studies are warranted to elucidate the underlying mechanisms of the VDR in development of ovarian cancer.
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Affiliation(s)
- Yanling Liu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - Chenglin Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - Peizhan Chen
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - Xiaoguang Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - Mian Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - He Guo
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
| | - Jingquan Li
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
- Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, P. R. China
| | - Ruiai Chu
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
- Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, P. R. China
| | - Hui Wang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, P. R. China
- Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, P. R. China
- * E-mail:
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Liu F, Wen B, Kayser M. Colorful DNA polymorphisms in humans. Semin Cell Dev Biol 2013; 24:562-75. [PMID: 23587773 DOI: 10.1016/j.semcdb.2013.03.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/26/2013] [Indexed: 10/26/2022]
Abstract
In this review article we summarize current knowledge on how variation on the DNA level influences human pigmentation including color variation of iris, hair, and skin. We review recent progress in the field of human pigmentation genetics by focusing on the genes and DNA polymorphisms discovered to be involved in determining human pigmentation traits, their association with diseases particularly skin cancers, and their power to predict human eye, hair, and skin colors with potential utilization in forensic investigations.
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Affiliation(s)
- Fan Liu
- Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Peña-Chilet M, Ibarrola-Villava M, Martin-González M, Feito M, Gomez-Fernandez C, Planelles D, Carretero G, Lluch A, Nagore E, Ribas G. rs12512631 on the group specific complement (vitamin D-binding protein GC) implicated in melanoma susceptibility. PLoS One 2013; 8:e59607. [PMID: 23544077 PMCID: PMC3609832 DOI: 10.1371/journal.pone.0059607] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 02/15/2013] [Indexed: 12/31/2022] Open
Abstract
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.
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Affiliation(s)
- Maria Peña-Chilet
- Medical Oncology and Haematology Unit, Health Research Institute INCLIVA, Valencia, Spain
| | | | | | - Marta Feito
- Dermatology Department, La Paz University Hospital, Madrid, Spain
| | | | - Dolores Planelles
- Laboratory of Histocompatibility-Molecular Biology, Centre for Blood Transfusion, Valencia, Spain
| | - Gregorio Carretero
- Dermatology Department, Doctor Negrín Hospital, Las Palmas de Gran Canaria, Spain
| | - Ana Lluch
- Medical Oncology and Haematology Unit, Health Research Institute INCLIVA, Valencia, Spain
| | - Eduardo Nagore
- Dermatology Department, Instituto Valenciano de Oncología, Valencia, Spain
| | - Gloria Ribas
- Medical Oncology and Haematology Unit, Health Research Institute INCLIVA, Valencia, Spain
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Ogbah Z, Visa L, Badenas C, Ríos J, Puig-Butille JA, Bonifaci N, Guino E, Augé JM, Kolm I, Carrera C, Pujana MÁ, Malvehy J, Puig S. Serum 25-hydroxyvitamin D3 levels and vitamin D receptor variants in melanoma patients from the Mediterranean area of Barcelona. BMC MEDICAL GENETICS 2013; 14:26. [PMID: 23413917 PMCID: PMC3648347 DOI: 10.1186/1471-2350-14-26] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 02/12/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Serum 25-hydroxyvitamin D3 (Vitamin D) insufficiency and single-nucleotide polymorphisms (SNPs) on its receptor, Vitamin D receptor (VDR), have been reported to be involved in melanoma susceptibility in populations mostly from northern countries. OBJECTIVE To investigate 25-hydroxyvitamin D3 levels and VDR SNPs in melanoma patients from sunny area of Barcelona, two studies were carried out. The first study evaluated the levels of Vitamin D at time of melanoma diagnosis and the second one analyzed the association between VDR genetic variants and risk of having a high nevus number, the strongest phenotypic risk factor for melanoma. METHODS The levels of 25-hydroxyvitamin D3 in 81 melanoma patients at diagnosis were measured. In a second group of melanoma patients, including 150 with low and 113 with high nevus number, 11 VDR SNPs were analyzed for their association with nevus number. RESULTS In the first study, 68% of patients had insufficient levels of 25-hydroxyvitamin D3 (<25 ng/ml). Autumn-winter months and fair phototype were associated with 25-hydroxyvitamin D3 insufficiency; after multivariate analysis, season of sampling remained the only independent predictor of 25-hydroxyvitamin D3 levels. In the second study, VDR variant rs2189480 (P = 0.006) was associated with risk of high nevus number whereas rs2239179 (P = 0.044) and rs7975128 (P = 0.0005) were protective against high nevus number. After Bonferroni adjustment only rs7975128 remained significant. In stratified analysis, SNP rs7975128 was found protective against multiple melanomas (P = 0.021). CONCLUSION This study showed that even in Barcelona, a sunny Mediterranean area, 25-hydroxyvitamin D3 levels were sub-optimal in the majority of melanoma patients at diagnosis. The involvement of VDR in nevi and, in turn, in melanoma susceptibility has also been suggested. Larger studies are needed to confirm our findings.
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Tang JY, Fu T, Lau C, Oh DH, Bikle DD, Asgari MM. Vitamin D in cutaneous carcinogenesis: part I. J Am Acad Dermatol 2013; 67:803.e1-12, quiz 815-6. [PMID: 23062903 DOI: 10.1016/j.jaad.2012.05.044] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 04/27/2012] [Accepted: 05/02/2012] [Indexed: 02/07/2023]
Abstract
Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.
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Affiliation(s)
- Jean Y Tang
- Department of Dermatology, Stanford University, Stanford, CA 94305, USA.
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Tang JY, Fu T, Lau C, Oh DH, Bikle DD, Asgari MM. Vitamin D in cutaneous carcinogenesis: part II. J Am Acad Dermatol 2013; 67:817.e1-11; quiz 827-8. [PMID: 23062904 DOI: 10.1016/j.jaad.2012.07.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 06/12/2012] [Accepted: 07/01/2012] [Indexed: 12/20/2022]
Abstract
The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.
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Affiliation(s)
- Jean Y Tang
- Department of Dermatology, Stanford University, Stanford, California 94305, USA.
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Berwick M, Erdei EO. Vitamin D and melanoma incidence and mortality. Pigment Cell Melanoma Res 2012; 26:9-15. [PMID: 22947439 DOI: 10.1111/pcmr.12015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 08/31/2012] [Indexed: 11/30/2022]
Abstract
The role of vitamin D (25-OH-D, or 25-hydroxyvitamin D) and its potential confounders in relationship to melanoma risk and mortality is discussed. The paradox that ultraviolet radiation (UVR) exposure is the major environmental risk factor for melanoma etiology as well as a major source of vitamin D might be explained by viewing vitamin D levels as the result of a healthy lifestyle rather than a cause of health.
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Affiliation(s)
- Marianne Berwick
- Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico Cancer Center, Albuquerque, NM, USA.
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Szyszka P, Zmijewski MA, Slominski AT. New vitamin D analogs as potential therapeutics in melanoma. Expert Rev Anticancer Ther 2012; 12:585-99. [PMID: 22594894 DOI: 10.1586/era.12.40] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Extensive evidence shows that the active form of vitamin D3--1α,25-dihydroxyvitamin D3--plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for secosteroids and new targets in the cells, which opens up new therapeutic possibilities.
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Affiliation(s)
- Paulina Szyszka
- Department of Histology, Medical University of Gdansk, Gdansk, Poland
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35
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Volkovova K, Bilanicova D, Bartonova A, Letašiová S, Dusinska M. Associations between environmental factors and incidence of cutaneous melanoma. Review. Environ Health 2012; 11 Suppl 1:S12. [PMID: 22759494 PMCID: PMC3388446 DOI: 10.1186/1476-069x-11-s1-s12] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
BACKGROUND Cutaneous melanoma is one of the most serious skin cancers. It is caused by neural crest-derived melanocytes - pigmented cells normally present in the epidermis and, sometimes, in the dermis. METHODS We performed a review of current knowledge on the risk factors of cutaneous melanoma. Relevant studies were identified using the PubMed, Science Direct, Medline, Scopus, Scholar Google and ISI Web of Knowledge databases. RESULTS Melanoma incurs a considerable public health burden owing to the worldwide dramatic rise in incidence since the mid-1960s. Ultraviolet radiation exposure is the predominant environmental risk factor. The role of geographical (latitude) and individual factors such as skin type, life style, vitamin D levels and antioxidant protection, sunburn, and exposure to other environmental factors possibly contributing to melanoma risk (such as cosmetics including sunscreen, photosensitising drugs, and exogenous hormones) are reviewed in this article. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified. CONCLUSIONS Cutaneous melanoma is a complex cancer with heterogeneous aetiology that continues to increase in incidence. Introduction of new biomarkers may help to elucidate the mechanism of pathogenesis and individual susceptibility to the disease, and make both prevention and treatment more effective.
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Affiliation(s)
| | - Dagmar Bilanicova
- Slovak Medical University, Bratislava, Slovakia
- University of Venice, Venice, Italy
| | | | | | - Maria Dusinska
- Slovak Medical University, Bratislava, Slovakia
- NILU - Norwegian Institute for Air Research, Oslo, Norway
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Nemazannikova N, Antonas K, Dass CR. Role of vitamin D metabolism in cutaneous tumour formation and progression. J Pharm Pharmacol 2012; 65:2-10. [PMID: 23215682 DOI: 10.1111/j.2042-7158.2012.01527.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Very limited information is available on the role of vitamin D in skin carcinogenesis. For most individuals, skin cancer can be readily managed with surgery; however, some patients may face life-threatening neoplasia. Sun exposure, specifically UV radiation, is a causative agent for development of skin cancer, though, somewhat ironically, sunlight through the production of vitamin D may have protective effect against some skin cancers. This review focuses on the development and progression of cutaneous carcinogenesis and the role of vitamin D in the prevention of the initiation and progression of lethal skin cancers. KEY FINDINGS Vitamin D is involved in regulation of multiple signalling pathways that have implications in carcinogenesis. Skin cancer metastasis depends on the tumour microenvironment, where vitamin D metabolites play a key role in prevention of certain molecular events involved in tumour progression. The vitamin D receptor (VDR) is a well-known potent regulator of cellular growth and differentiation. SUMMARY The VDR's possible involvement in cell death, tumour microenvironment and angiogenesis makes it a candidate agent for cancer regulation.
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Affiliation(s)
- Natalie Nemazannikova
- School of Biomedical and Health Sciences, Victoria University, St Albans, Victoria, Australia
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Denzer N, Vogt T, Reichrath J. Vitamin D receptor (VDR) polymorphisms and skin cancer: A systematic review. DERMATO-ENDOCRINOLOGY 2011. [PMID: 22110781 DOI: 10.4161/derm.3.3.16519.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Skin cancer is the most common cancer in humans. There are several types of skin cancer that include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). The associations of vDr polymorphisms with skin cancer risk are not well characterized so far. Only a few epidemiologic studies have directly addressed the relationship between VDR polymorphisms and the incidence and prognosis of MM. To make the most of the available information on VDR polymorphisms and skin cancer (MM, BCC and SCC), we undertook a systematic review of published studies. In conclusion, data summarized in this review support the concept that the vitamin D endocrine system (VDES) is of importance for pathogenesis and progression of MM and other types of skin cancer.
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Affiliation(s)
- Nicole Denzer
- Department of Dermatology; The Saarland University Hospital; Homburg, Germany
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Lee JH, Park S, Cheon S, Lee JH, Kim S, Hur DY, Kim TS, Yoon SR, Yang Y, Bang SI, Park H, Lee HT, Cho D. 1,25-Dihydroxyvitamin D3 enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression. Eur J Immunol 2011; 41:2937-46. [DOI: 10.1002/eji.201141597] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 07/04/2011] [Accepted: 07/21/2011] [Indexed: 01/09/2023]
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Chatzinasiou F, Lill CM, Kypreou K, Stefanaki I, Nicolaou V, Spyrou G, Evangelou E, Roehr JT, Kodela E, Katsambas A, Tsao H, Ioannidis JPA, Bertram L, Stratigos AJ. Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst 2011; 103:1227-35. [PMID: 21693730 PMCID: PMC4719704 DOI: 10.1093/jnci/djr219] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Revised: 05/03/2011] [Accepted: 05/05/2011] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported. METHODS We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided. RESULTS Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility. CONCLUSIONS To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.
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Affiliation(s)
- Foteini Chatzinasiou
- Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Dragoumi 5, Athens 161 21, Greece
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Vitamin D and cancer: deciphering the truth. Biochim Biophys Acta Rev Cancer 2011; 1816:172-8. [PMID: 21767609 DOI: 10.1016/j.bbcan.2011.07.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Revised: 07/01/2011] [Accepted: 07/04/2011] [Indexed: 12/23/2022]
Abstract
Vitamin D is a hormone-like micronutrient involved not only in calcium metabolism but also in a variety of biological activities (e.g., cell proliferation, apoptosis, angiogenesis, inflammation) that makes it a candidate anticancer agent. Preclinical studies support the therapeutic potential of vitamin D both alone and in combination with other therapeutics. Overall, epidemiological data suggest the existence of a link between vitamin D and cancer risk, whereas the results of clinical trials are quite conflicting. This article is a comprehensive and balanced overview of the current evidence in an attempt to critically interpret the wealth of scientific data thus far produced on this research field and to rationally envisage the next steps necessary to define the role of vitamin D in the therapeutic management of cancer.
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Denzer N, Vogt T, Reichrath J. Vitamin D receptor (VDR) polymorphisms and skin cancer: A systematic review. DERMATO-ENDOCRINOLOGY 2011; 3:205-10. [PMID: 22110781 DOI: 10.4161/derm.3.3.16519] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 05/07/2011] [Accepted: 05/18/2011] [Indexed: 01/10/2023]
Abstract
Skin cancer is the most common cancer in humans. There are several types of skin cancer that include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). The associations of vDr polymorphisms with skin cancer risk are not well characterized so far. Only a few epidemiologic studies have directly addressed the relationship between VDR polymorphisms and the incidence and prognosis of MM. To make the most of the available information on VDR polymorphisms and skin cancer (MM, BCC and SCC), we undertook a systematic review of published studies. In conclusion, data summarized in this review support the concept that the vitamin D endocrine system (VDES) is of importance for pathogenesis and progression of MM and other types of skin cancer.
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Affiliation(s)
- Nicole Denzer
- Department of Dermatology; The Saarland University Hospital; Homburg, Germany
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Macbeth AE, Grindlay DJC, Williams HC. What's new in skin cancer? An analysis of guidelines and systematic reviews published in 2008-2009. Clin Exp Dermatol 2011; 36:453-8. [PMID: 21671988 DOI: 10.1111/j.1365-2230.2011.04087.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
This review summarizes clinically important findings from 17 systematic reviews and 2 guidelines on skin cancer indexed between April 2008 and April 2009. Melanoma primary-prevention measures, such as education, are more likely to be successful in younger children than adolescents, and general population screening for melanoma by whole-body examination is not currently supported by the evidence. A large systematic review of melanoma and pregnancy concluded that pregnancy does not affect prognosis. Two systematic reviews imply that sunburn later in life also increases the risk of melanoma, and that it is just as important as sunburn early in life. Three systematic reviews discussed the role of positron emission tomography and sentinel lymph-node biopsy for melanoma staging, but produced conflicting results. Superior diagnostic accuracy of dermatoscopy over naked-eye examination for melanoma was found in one review, while a second implied nonsignificantly higher sensitivity of computer-based diagnostic methods over dermatoscopy for melanoma but with reduced specificity. There were no identified randomized controlled trials of treatments for unresectable recurrent melanoma, and a review of immunotherapy with vaccines for melanoma failed to prove improved overall and disease-free survival. Guidelines for the management of basal cell carcinoma call for risk stratification, based on numerous factors including tumour size, site and histological subtype. Squamous cell carcinoma of the ear has been shown to spread to regional lymph nodes more commonly than to other sites, and may be predicted by depth of invasion, tumour size, cellular differentiation and completeness of excision.
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Affiliation(s)
- A E Macbeth
- Department of Dermatology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
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Orlow I, Roy P, Reiner AS, Yoo S, Patel H, Paine S, Armstrong BK, Kricker A, Marrett LD, Millikan RC, Thomas NE, Gruber SB, Anton-Culver H, Rosso S, Gallagher RP, Dwyer T, Kanetsky PA, Busam K, From L, Begg CB, Berwick M. Vitamin D receptor polymorphisms in patients with cutaneous melanoma. Int J Cancer 2011; 130:405-18. [PMID: 21365644 DOI: 10.1002/ijc.26023] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Accepted: 02/08/2011] [Indexed: 01/24/2023]
Abstract
The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.
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Affiliation(s)
- Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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Brożyna AA, Jozwicki W, Janjetovic Z, Slominski AT. Expression of vitamin D receptor decreases during progression of pigmented skin lesions. Hum Pathol 2011; 42:618-31. [PMID: 21292298 DOI: 10.1016/j.humpath.2010.09.014] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Revised: 09/21/2010] [Accepted: 09/22/2010] [Indexed: 01/18/2023]
Abstract
1,25-dihydroxyvitamin D3 affects proliferation, differentiation, and apoptosis and protects DNA against oxidative damage with a net tumorostatic and anticarcinogenic effect. It acts through a specific nuclear receptor that is widely distributed through the body. Although a beneficial role of vitamin D in melanoma patients has been suggested, there is lack of information on the changes in the expression pattern of vitamin D receptor during progression of pigmented lesions. Using immunohistochemistry, we analyzed the expression of vitamin D receptor in 140 samples obtained form 82 patients, including 25 benign nevi, 70 primary cutaneous melanomas, 35 metastases, 5 re-excisions, and 5 normal skin biopsies. The strongest expression was observed in normal skin that significantly decreased in melanocytic proliferations with the following order of expression: normal skin > melanocytic nevi > melanomas = metastases. The vitamin D receptor expression in skin surrounding nevi and melanoma was also significantly reduced as compared to normal skin. Tumor-infiltrating and lymph node lymphocytes retained high levels of vitamin D receptor. There was negative correlation between tumor progression and vitamin D receptor expression with a remarkable decrease of the immunoreactivity in nuclei of melanoma cells at vertical versus radial growth phases and with metastatic melanomas showing the lowest cytoplasmic receptor staining. Furthermore, lack of the receptor expression in primary melanomas and metastases was related to shorter overall patients' survival. In addition, the receptor expression decreased in melanized melanoma cells in comparison to amelanotic or poorly pigmented cells. Therefore, we propose that reduction or absence of vitamin D receptor is linked to progression of melanocytic lesions, that its lack affects survival of melanoma patients, and that melanogenesis can attenuate receptor expression. In conclusion, changes in vitamin D receptor expression pattern can serve as important variables for diagnosis, predicting clinical outcome of the disease, and/or as a guidance for novel therapy of melanomas based on use of vitamin D or its derivatives.
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Affiliation(s)
- Anna A Brożyna
- Department of Tumor Pathology and Pathomorphology, The Lukaszczyk Oncology Center, The Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz 85-796, Poland
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Pinczewski J, Slominski A. The potential role of vitamin D in the progression of benign and malignant melanocytic neoplasms. Exp Dermatol 2010; 19:860-4. [PMID: 20872994 PMCID: PMC2947742 DOI: 10.1111/j.1600-0625.2010.01169.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hormonally active vitamin D3, 1,25-(OH)2D3, is believed to have a role in the prevention of cancer formation and in limiting the aggressiveness of cancers that do arise. Therefore,much interest is presently being focused on 1,25-(OH)2D3 and its analogues as potential treatments for various cancers including melanoma. This article discusses the evidence in favour of a role for 1,25-(OH)2D3 in protection against the progression of melanocytic lesions and also summarizes the mechanisms by which 1,25-(OH)2D3 may act to protect against melanoma development and progression.
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Affiliation(s)
- Joel Pinczewski
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
- Division of Dermatology and Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Andrzej Slominski
- Division of Dermatology and Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
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Chan SH, Stoddard BL, Xu SY. Natural and engineered nicking endonucleases--from cleavage mechanism to engineering of strand-specificity. Nucleic Acids Res 2010; 39:1-18. [PMID: 20805246 PMCID: PMC3017599 DOI: 10.1093/nar/gkq742] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Restriction endonucleases (REases) are highly specific DNA scissors that have facilitated the development of modern molecular biology. Intensive studies of double strand (ds) cleavage activity of Type IIP REases, which recognize 4–8 bp palindromic sequences, have revealed a variety of mechanisms of molecular recognition and catalysis. Less well-studied are REases which cleave only one of the strands of dsDNA, creating a nick instead of a ds break. Naturally occurring nicking endonucleases (NEases) range from frequent cutters such as Nt.CviPII (^CCD; ^ denotes the cleavage site) to rare-cutting homing endonucleases (HEases) such as I-HmuI. In addition to these bona fida NEases, individual subunits of some heterodimeric Type IIS REases have recently been shown to be natural NEases. The discovery and characterization of more REases that recognize asymmetric sequences, particularly Types IIS and IIA REases, has revealed recognition and cleavage mechanisms drastically different from the canonical Type IIP mechanisms, and has allowed researchers to engineer highly strand-specific NEases. Monomeric LAGLIDADG HEases use two separate catalytic sites for cleavage. Exploitation of this characteristic has also resulted in useful nicking HEases. This review aims at providing an overview of the cleavage mechanisms of Types IIS and IIA REases and LAGLIDADG HEases, the engineering of their nicking variants, and the applications of NEases and nicking HEases.
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Falleti E, Bitetto D, Fabris C, Cussigh A, Fontanini E, Fornasiere E, Fumolo E, Bignulin S, Cmet S, Minisini R, Pirisi M, Toniutto P. Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis. World J Gastroenterol 2010; 16:3016-24. [PMID: 20572305 PMCID: PMC2890942 DOI: 10.3748/wjg.v16.i24.3016] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the relationship between vitamin D receptor (VDR) gene polymorphisms and the presence of hepatocellular carcinoma (HCC).
METHODS: Two-hundred forty patients who underwent liver transplantation were studied. The etiologies of liver disease were hepatitis C (100 patients), hepatitis B (37) and alcoholic liver disease (103). A group of 236 healthy subjects served as controls. HCC in the explanted liver was detected in 80 patients. The following single nucleotide gene polymorphisms of the VDR were investigated by polymerase chain reaction and restriction fragment length polymorphism: FokI C>T (F/f), BsmI A>G (B/b), ApaI T>G (A/a) and TaqI T>C (T/t) (BAT).
RESULTS: The frequencies of genotypes in patients without and with HCC were for FokI F/F = 69, F/f = 73, f/f = 18 and F/F = 36, F/f = 36, f/f = 8; BsmI b/b = 45, B/b = 87, B/B = 28 and b/b = 33, B/b = 35, B/B = 12; for ApaI A/A = 53, A/a = 85, a/a = 22 and A/A = 27, A/a = 38, a/a = 15; for TaqI T/T = 44, T/t = 88, t/t = 28 and T/T = 32, T/t = 38, t/t = 10. Carriage of the b/b genotype of BsmI and the T/T genotype of TaqI was significantly associated with HCC (45/160 vs 33/80, P < 0.05 and 44/160 vs 32/80, P < 0.05, respectively). The absence of the A-T-C protective allele of BAT was significantly associated with the presence of HCC (46/80 vs 68/160, P < 0.05). A strong association was observed between carriage of the BAT A-T-C and G-T-T haplotypes and HCC only in alcoholic liver disease (7/46 vs 12/36 vs 11/21, P < 0.002, respectively).
CONCLUSION: VDR genetic polymorphisms are significantly associated with the occurrence of HCC in patients with liver cirrhosis. This relationship is more specific for patients with an alcoholic etiology.
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Reichrath J, Nürnberg B. Cutaneous vitamin D synthesis versus skin cancer development: The Janus faces of solar UV-radiation. DERMATO-ENDOCRINOLOGY 2009; 1:253-61. [PMID: 20808512 PMCID: PMC2836430 DOI: 10.4161/derm.1.5.9707] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Accepted: 07/30/2009] [Indexed: 01/09/2023]
Abstract
In scientific and public communities, there is an ongoing discussion how to balance between positive and negative effects of solar UV-exposure. On the one hand, solar UV-radiation represents the most important environmental risk factor for the development of non-melanoma skin cancer. Consequently, UV protection is an important measure to prevent these malignancies, especially in risk groups. Otherwise, approximately 90% of all vitamin D needed by the human body has to be formed in the skin through the action of UV-radiation. This dilemma represents a serious problem, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer, bone diseases, autoimmune diseases, infectious diseases, cardiovascular diseases and hypertension has now been reported in a large number of investigative and epidemiologic studies. As a consequence, it has been assumed that for the general population in the US, Europe and other countries, the net effects of solar UV B-radiation on human health are beneficial at or near current levels. We and others have shown that strict sun protection causes vitamin D-deficiency/insufficiency and that detection and treatment of vitamin D-deficiency in sun deprived risk groups is of high importance. Although further work is necessary to define an adequate vitamin D-status and adequate guidelines for solar and artificial UV-exposure, it is at present mandatory that public health campaigns and sun protection recommendations to prevent skin cancer consider these facts. In this review, we analyze the present literature to help developing well-balanced recommendations on sun protection that ensure an adequate vitamin D-status. These recommendations will hopefully protect us against adverse effects of UV protection without significantly increasing the risk to develop UV-induced skin cancer.
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Affiliation(s)
- Jörg Reichrath
- Klinik für Dermatologie; Venerologie und Allergologie; Universitätsklinikum des Saarlandes; Homburg/Saar, Germany
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Mocellin S, Verdi D, Nitti D. DNA repair gene polymorphisms and risk of cutaneous melanoma: a systematic review and meta-analysis. Carcinogenesis 2009; 30:1735-43. [PMID: 19706646 DOI: 10.1093/carcin/bgp207] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding the relationship between these polymorphisms and the risk of developing cutaneous melanoma. Relevant studies were searched using PubMed, Medline, Embase, Cancerlit, Cochrane and ISI Web of Knowledge databases. Data were gathered according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The model-free approach was adopted to perform the meta-analysis of the retrieved data. We identified 20 original reports that describe the relationship between melanoma risk and the single-nucleotide polymorphisms (SNPs) of 16 genes (cases = 4195). For seven SNPs considered in at least two studies, the findings were heterogeneous. Data were suitable for meta-analysis only in the case of the XPD/ERCC2 SNP rs13181 (cases = 2308, controls = 3698) and demonstrated that the variant C allele is associated with increased melanoma risk (odds ratio = 1.12, 95% confidence interval = 1.03-1.21, P = 0.01; population attributable risk = 9.6%). This is the first meta-analysis suggesting that XPD/ERCC2 might represent a low-penetrance melanoma susceptibility gene. Much work is still to be done before definitive conclusions can be drawn on the role of DNA repair alterations in melanomagenesis since for the other genes involved in this highly complex process, the available information is scarce or null.
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Affiliation(s)
- Simone Mocellin
- Department of Oncological and Surgical Sciences, Meta-analysis Unit, University of Padova, Padova, Italy.
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Udayakumar D, Tsao H. Melanoma genetics: an update on risk-associated genes. Hematol Oncol Clin North Am 2009; 23:415-29, vii. [PMID: 19464594 DOI: 10.1016/j.hoc.2009.03.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The past 15 years have seen rapid advances in both our understanding of hereditary melanoma genetics and the technologies that enable scientists to make discoveries. Despite great efforts by many groups worldwide, other high-risk melanoma loci besides CDKN2A still remain elusive. A panel of polymorphisms that appears to confer low-to-moderate risk for melanoma has been assembled through functional and genome-wide association studies. The goal of personalized melanoma risk prediction is within our reach, although true clinical use has yet to be established.
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Affiliation(s)
- Durga Udayakumar
- Department of Dermatology, Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, Edwards 211, 50 Blossom Street, Boston, MA 02114, USA
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