Novel MC1R variants in Ligurian melanoma patients and controls

Pastorino, Lorenza; Cusano, Roberto; Bruno, William; Lantieri, Francesca; Origone, Paola; Barile, Mônica; Gliori, Sara; Shepherd, Graeme; Sturm, Richard A.; Scarrà, Giovanna Bianchi

doi:10.1002/humu.9253

Cited by 41 publications

(45 citation statements)

References 19 publications

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“…Numerous studies have negated involvement of this gene in determination of iris colour variation (Branicki et al 2005). Initial data suggest that epistatic interactions between different genes may also play an important role in eventual determination of phenotypic features (Akey et al 2001;Pastorino et al 2004). Pastorino et al (2004) suggested that MC1R variants that are responsible for red hair colour determination may be masked by other genes in populations with darker pigmentation.…”

Section: Resultsmentioning

confidence: 99%

“…Some allelic variants of the MC1R gene are significantly associated with the overproduction of pheomelanin and therefore red hair and fair skin colour (Rees 2003). Most studies are in agreement that MC1R is involved in malignant melanoma and basal cell carcinoma (e.g., Pastorino et al 2004;Kanetsky et al 2006;Brudnik et al 2008). It is postulated that a product of the ASIP gene may antagonize MC1R receptor activation (Voisey and Van Daal 2002).…”

Section: Introductionmentioning

confidence: 96%

“…Nowadays, red hair phenotype is being predicted using assays that rely on examination of the single MC1R gene, and this allows correct inference in more than 90% of cases (Grimes et al 2001;Branicki et al 2007). Future assays ought to be more relevant in this matter as they should take into account differences that have been noticed in red hair colour inheritance for various populations and perhaps encompass analysis of additional genes (Pastorino et al 2004). Studies that have disclosed the significance of the HERC2 and OCA2 genes in iris colour inheritance are also a milestone towards eye colour prediction Frudakis et al 2003;Kayser et al 2008;Sturm et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Association of the SLC45A2 gene with physiological human hair colour variation

et al. 2008

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Pigmentation is a complex physical trait with multiple genes involved. Several genes have already been associated with natural differences in human pigmentation. The SLC45A2 gene encoding a transporter protein involved in melanin synthesis is considered to be one of the most important genes affecting human pigmentation. Here we present results of an association study conducted on a population of European origin, where the relationship between two non-synonymous polymorphisms in the SLC45A2 gene -rs26722 (E272K) and rs16891982 (L374F) -and different pigmentation traits was examined. The study revealed a significant association between both variable sites and normal variation in hair colour. Only L374F remained significantly associated with hair colour when both SNPs were included in a logistic regression model. No association with other pigmentation traits was detected in this population sample. Our results indicate that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker for black hair colour prediction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Association of the SLC45A2 gene with physiological human hair colour variation

et al. 2008

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“…[28][29][30][31] In addition, a previous study on Italian melanoma cases and controls showed that homozygosity or compound heterozygosity for high penetrance MC1R variants was not necessarily associated with red hair color. 28 Whether the lack of a melanoma-MC1R association in the Italian sample observed here reflects low power, family-based case selection, or differential risk in G101W carriers requires further examination.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

Goldstein

Chaudru

Ghiorzo

et al. 2007

Intl Journal of Cancer

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The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had 2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. ' 2007 Wiley-Liss, Inc.Key words: melanoma; CDKN2A; MC1R; G101W Germline mutations within the coding region of the CDKN2A gene (9p21) have been observed in affected members of melanoma-prone families. 1,2 G101W is one of the most common CDKN2A missense mutations identified to date. It is the most common mutation observed in Italy, Spain, and France. G101W also has a high occurrence in the United States. Similar to most of the other frequent recurrent CDKN2A mutations, G101W appears to have resulted from a single mutational event. Previous evaluation of 20 melanoma-prone families with G101W mutations from France, Italy, and the United States provided compelling evidence for a single genetic origin for G101W; the mutation was estimated to have originated about 97 generations ago (1 LODunit support interval 70-133 generations). 3 Although CDKN2A mutations confer substantial risk for melanoma, not all carriers of mutations develop melanoma. Other host/ clinical, environmental, and genetic factors also modulate risk. It is well known that the incidence of melanoma varies worldwide and even in the context of familial melanoma, penetrance of CDKN2A mutations differs between Europe and the United States. 4 These differences could be related to different genetic backgrounds or to variation in host/clinical characteristics and/or sun behavior. Pr...

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“…2). Studies also have focused on the relationship of MC1R with development of malignant melanoma (3)(4)(5)(6)(7)(8). Results from these studies have shown that MC1R variants and particularly those variants most strongly associated with red hair color (termed R variants, including D84E, R151C, R160W, and D294H; see ref.…”

Section: Introductionmentioning

confidence: 99%

Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma

Kanetsky

Rebbeck²,

Hummer³

et al. 2006

Cancer Research

110

115

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Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international populationbased study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency >1%. Compared with controls, cases were more likely to carry two previously identified red hair (''R'') variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design. (Cancer Res 2006; 66(18): 9330-7)

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Novel MC1R variants in Ligurian melanoma patients and controls

Cited by 41 publications

References 19 publications

Association of the SLC45A2 gene with physiological human hair colour variation

Association of the SLC45A2 gene with physiological human hair colour variation

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma

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