ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Guðbjartsson, Daníel F.; Sulem, Patrick; Stacey, Simon; Goldstein, Alisa M.; Rafnar, Thorunn; Sigurgeirsson, Bárður; Benediktsdóttir, Kristrún R.; Thorisdottir, Kristin; Ragnarsson, Rafn; Sveinsdottir, Steinunn G; Magnusson, Veronica; Lindblom, Annika; Kostulas, Konstantinos; Botella‐Estrada, Rafael; Soriano, Virtudes; Juberías, Pablo; Grasa, Matilde; Sáez, Berta; Andrés, Raquel; Scherer, Dominique; Rudnai, Péter; Gurzău, Eugen; Koppová, Kvetoslava; Kiemeney, Lambertus A.; Jakobsdottir, Margret; Steinberg, Stacy; Helgason, Agnar; Grétarsdóttir, Sólveig; Tucker, Margaret A.; Mayordomo, J. I.; Nagore, Eduardo; Kumar, Rajiv; Hansson, Johan; Ólafsson, Jón; Gulcher, Jeffrey R.; Kong, Augustine; Þorsteinsdóttir, Unnur; Stefánsson, Kāri

doi:10.1038/ng.161

Cited by 303 publications

(323 citation statements)

References 30 publications

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“…This may be explained in part by the higher frequency of a family history of MM in the MM þ RCC series compared with the MM series, because it is known that MM-associated phenotypes cluster in families and that genetic variants influence both host factors and MM. 5 However, we observed that the distribution of these risk factors did not differ significantly between patients in the MM þ RCC series with and without a family history (results not shown).…”

Section: Discussionmentioning

confidence: 69%

Characteristics of the coexistence of melanoma and renal cell carcinoma

Maubec

Chaudru

Mohamdi

et al. 2010

Cancer

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BACKGROUND:Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association. METHODS: Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM þ RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series). RESULTS: RCC was diagnosed concomitantly or after MM in 83% of patients in the MM þ RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM þ RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM þ RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P ¼ .005). Only 2 cyclin-dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM þ RCC series who also were members of MM-prone families. CONCLUSIONS: The high aggregation of cancers among patients in the MM þ RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A. Cancer 2010;116:5716-24.

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Section: Discussionmentioning

confidence: 69%

Characteristics of the coexistence of melanoma and renal cell carcinoma

Maubec

Chaudru

Mohamdi

et al. 2010

Cancer

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“…In light of the correlation of MC1R variants with increased skin cancer risk, and considering the tumorigenic effects of ASP, one can expect that ASP would contribute to melanoma and/or other skin cancer risk. Interestingly, 2 different groups reported an association between variants on chromosome 20q11.22, which lies in the vicinity of ASIP, and cutaneous melanoma and basal cell carcinoma (30,31). Although further studies will be necessary to confirm whether ASIP is the causal variant, a growing body of evidence supports this hypothesis.…”

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confidence: 99%

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Pape

Passeron

Giubellino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by ␣-melanocyte stimulating hormone (␣MSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or ␣MSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by ␣MSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk.pigmentation ͉ skin cancer A major determinant of the pigment phenotype of the skin is the melanocortin-1 receptor (MC1R), a G protein coupled receptor (GPCR) that regulates many functional aspects of melanocytes, including their dendricity, melanogenesis, and proliferation (1, 2). MC1R function can be activated by ␣-melanocyte-stimulating hormone (␣MSH), a POMC-derived peptide whose production in the skin (3) is increased by exposure to UV radiation (UV) via a p53-dependent mechanism (4). This interaction triggers increased melanin production (5, 6) and stimulates the repair of DNA photoproducts caused by UV (7-9), a phenomenon also induced by forskolin (10). It is therefore not surprising that MC1R polymorphisms are associated with a lighter pigment phenotype, including red hair/fair skin (11), with poor tanning responses (12) and an increased risk for melanoma and other skin cancers (13,14).MC1R signaling can be inhibited by the product of the agouti locus, agouti signal protein (ASP in mice, ASIP in humans), which acts as an inverse agonist of the murine Mc1r (15,16). In mice, ASP is expressed in skin and testis and during embryogenesis. The spatiotemporal expression of ASP in skin is responsible for the agouti hair phenotype (a pheomelanic band against a dark eumelanic background) and for the pale coloration on the neck, breast, and ventral surface (17). A high degree of polymorphism in the promoter of t...

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“…Recently, various genetic polymorphisms related to pigmentation have been associated with a high risk of developing melanoma in humans (GUDBJARTSSON et al, 2008). These factors combined with constant exposure to solar radiation may have contributed to the development of skin malignancies in albino water buffalo.…”

Section: Case Reportmentioning

confidence: 99%

Melanoma maligno em búfalos (Bubalus bubalis) albinos

et al. 2015

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Two albino water buffalo affected by multiple melanocytic tumors in Southern Brazil are described. Grossly, there were multiple dark tumors within the skin, skeletal muscle, lungs, and lymph nodes. The tumor was also present in the pericardial sac, renal capsule, mediastinum and pleura. Microscopically, the tumors consisted of polyhedral epithelioid cells arranged in solid nests or interwoven fascicles supported by a thin and sparse collagenous stroma. The cytoplasm was eosinophilic and sometimes contained varying amounts of melanin pigment. The mitotic rates were low. Immunohistochemistry staining with Tyrosinase, Melan-A, Vimentin, S-100 protein, and neurofilament were positive. It is possible that the polymorphisms related to pigmentation in albino buffalo contributed with a high risk of developing melanoma as suggested in humans. Key words: Albinism, water buffalo, immunohistochemistry, malignant melanoma ResumoDescrevem-se melanomas múltiplos em dois búfalos albinos da raça Murrah no Sul do Brasil. Macroscopicamente havia múltiplos tumores enegrecidos no músculo esquelético, pulmões, linfonodos, saco pericárdio, cápsula renal, mediastino e pleura. Microscopicamente foram observadas células epitelióides poliédricas dispostas em ninhos sólidos ou fascículos entrelaçados sustentadas por um estroma colagenoso fino e esparso. O citoplasma era eosinofílico e por vezes continham quantidades variáveis de pigmento de melanina. A taxa de mitose foi baixa. Na imuno-histoquímica houve imunomarcação positiva utilizando anticorpo anti-tirosinase, anti-Melan-A, anti-vimentina, anti-proteína S-100 e antineurofilamento. É possível que o polimorfismo relacionado com o gene da pigmentação em búfalos albinos tenha contribuído para o maior risco de desenvolvimento de melanomas, como foi sugerido em humanos. Palavras-chave: Albinismo, búfalos, imuno-histoquímica, melanoma 1 Médica Veterinária, Drª Pesquisadora, EMBRAPA Clima Temperado, Capão do Leão, RS, Brasil.

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ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Cited by 303 publications

References 30 publications

Characteristics of the coexistence of melanoma and renal cell carcinoma

Characteristics of the coexistence of melanoma and renal cell carcinoma

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Melanoma maligno em búfalos (Bubalus bubalis) albinos

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