The relation between melanocortin 1 receptor (MC1R) variation and the generation of phenotypic diversity in the cutaneous response to ultraviolet radiation

Wong, Terence H.; Rees, Jonathan

doi:10.1016/j.peptides.2004.11.021

Cited by 54 publications

(60 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to other reports (23,24), the occurrence of a variant in the first 50 codons of MC1R was rare in our data. Thus, we allowed an individual to be missing up to 150 nucleotides at the 5 ¶-end of the MC1R coding region due to weak sequence signal, which occurred in 698 (22%) sequenced individuals.…”

Section: Resultssupporting

confidence: 92%

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

Kanetsky

Rebbeck²,

Hummer³

et al. 2006

Cancer Research

110

115

View full text Add to dashboard Cite

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)

show abstract

Section: Resultssupporting

confidence: 92%

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

Kanetsky

Rebbeck²,

Hummer³

et al. 2006

Cancer Research

110

115

View full text Add to dashboard Cite

show abstract

“…These reports suggest that there is room for the non-functional variant alleles of the MC1R gene to play roles in pigmentation variation in Asians. Phe147D, Thr157Ile, Pro159Thr, and Ala166Gly alleles were not reported in Europeans in spite of the large-scale screening for MC1R polymorphisms (Wong and Rees 2005;Makova and Norton 2005). These private alleles arose on Val92Met, Ile120Thr, and Arg163Gln alleles, which were found with much higher frequencies in several East and Southeast Asians than in European populations (Rana et al 1999;Harding et al 2000;Yao et al 2000;Peng et al 2001;Fargnoli et al 2003;Na et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians

et al. 2006

View full text Add to dashboard Cite

Human melanocortin 1 receptor (MC1R) is a seven transmembrane G-coupled protein receptor that upregulates the cAMP pathway. Several functional variants of MC1R that show an impaired ability to activate the cAMP pathway are strongly associated with fair skin and red hair in Europeans and European descendants. The sequence variations of the MC1R gene were repeatedly investigated against worldwide populations; however, there was no evidence that functional variant of MC1R exists in non-European descendants. We report the presence of novel functional variants of MC1R with Asian origins. Three novel variants of MC1R, Phe147Delta, Thr157Ile, and Pro159Thr, were identified in our screening for the sequence variations of the MC1R gene against 995 individuals from 30 Asian and Oceanian populations; there was a single case for the Pro159Thr variant allele and two instances of Phe147Delta and Thr157Ile variant alleles. Our pharmacological assay revealed that Phe147Delta, Thr157Ile, and Pro159Thr variant showed similar or more dramatically impaired activities in comparison with Arg151Cys, which is a major functional variant of MC1R in Europeans. These functional variant alleles were geographically localized in relatively high latitudes, which suggest that the adaptation to ambient UV light intensity may play an important role in shaping the geographical distribution of MC1R alleles in Asia and Oceania.

show abstract

“…Melanin production, one of the main functions of melanocytes, is stimulated by a-melanocyte stimulating hormone (aMSH) (Figure 1). This hormone is secreted by keratinocytes and binds to the melanocortin 1 receptor, MC1R (Sturm, 2002;Wong and Rees, 2005). This G protein-coupled receptor triggers the cyclic adenosine mono-phosphate (cAMP) pathway in a protein kinase A (PKA)-dependent fashion.…”

Section: Braf Mutations In Malignant Tumoursmentioning

confidence: 99%

BRAFE600 in benign and malignant human tumours

et al. 2007

View full text Add to dashboard Cite

Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF E600 -expressing human tumour cells. Although BRAF E600 acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF E600 signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF E600 in benign and malignant human tumours and the implications for therapeutic intervention.

show abstract

The relation between melanocortin 1 receptor (MC1R) variation and the generation of phenotypic diversity in the cutaneous response to ultraviolet radiation

Cited by 54 publications

References 59 publications

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

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

Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians

BRAFE600 in benign and malignant human tumours

Contact Info

Product

Resources

About