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Title: Melanocortin-1 receptor gene and Agouti signaling protein polymorphisms and the risk of melanoma and basal cell carcinoma

Abstract:

Introduction Risk of cutaneous melanoma and basal cell carcinoma is very closely connected with sun exposure and skin phototype. Patients with fair skin complexion, who hardly get a suntan, easily sunburn and additionally are exposed to high doses of UV radiation, have predisposition to these skin cancers. The risk of having melanoma or basal cell carcinoma is a complex interplay between personal predisposition and environmental factors. Melanocortin-1 receptor gene may play a role in a skin cancer development. Human pigmentation depends on eumelanin and pheomelanin ratio. The type of the , produced melanin is connected to MC1R status. The frequency of MC1R polymorphisms varies in different populations and together with pigment phenotype determines personal skin cancer risk. ASIP (Agouti Signaling Protein) gene is the second gene that potentially plays a role in the melanogenesis. In mice ASIP protein binded to MC1 R antagonizes MSH activation of the receptor, which results in eumelanin underproduction and pheomelanin prevalence. Two ASIP variants have been identified so far, which differ in one nucleotide position, 8818A>G mutation probably leads to excessive transcript degradation and eumelanin production. This mutation may be responsible for masking of the effects of MC1 R gene variants predisposing to fair phenotype. Aim of the study The main purpose of th ; is study was to evaluate whether there is correlation between MC1R and ASIP variants and patients' phenotypes and also if there is a link between these genes and presence of cutaneous melanoma or basal cell carcinoma. We also sought association between specific MC 1 R variants, A8818G polymorphisms and pigment phenotype and skin cancers. An additional goal of this study was to prepare quick test to analyse specific MC1R nucleotide position for allele variants that we had found to be associated with skin cancer risk in a Polish population. Patients and methods We enrolled 210 patients (108 patients with skin melanoma and 102 patients with basal cell carcinoma). Additionally we included into the study 30 healty individuals with RHC phenotype. Control group consisted of 93 non-red hair patients, without history of skin cancers. Each person had assessed: skin phototype according to Fitzpatrick scale, nevi and freckle number localized on sun-exposed areas (face, neck, the upper part of the back, dorsal aspect of the hands) and also on covered areas (buttocks, breast in women). During the first visit we filled for each subject questionnaire containing phenotypic features data (skin type, mole and freckle count, and also eye and hair colour). We collected buccal swabs from every person for the purpose of genetic analysis. Samples were subjected to DNA isolation which was don ; e by standard organic method or with the use of SwabDNA kit. DNA concentration was measured with fluorimetric method. Then complete MC1R exon was amplified. PCR products were purified and subjected to cycle sequencing. The specific nucleotide positions of the MC1R gene were analysed using minisequencing method. To analyse A8818G polymorphism we used PCR primers allowing to amplificate gene fragment containing this position. Results and conclusions At least one MC1 R allelic variant was present in 70% of the subjects from a control group, which confirms that this gene is highly polymorphic in a Polish population. Allele G frequency was 3% in the control group. We confirmed MC1R gene significant influence on presence of fair phenotype. Subjects with "major function mutations"-R significantly more frequently had phototype I or II with medium or high freckle count and red or blond hair colour. The presence of a variant allele correlated with the mole count; R151C, R160W, 0294H variants were more common in subjects without or with fewer number of nevi. Our results together with data from the literature neglect MC1R influence on melanoma risk through the number of moles. We did not found correlation between ASIP variants and phenotypic characteristics of the studied subjects. The MC1R genotype was associated with cutaneous melanoma risk. This correlation was the most significant ; for R151C, R160W variants. Obtained results confirm previous observations that the presence of MC1R gene mutations independently increases melanoma risk; we did not show modifying influence of the eye colour, skin phototype, hair colour, presence of nevi or freckles on this correlation. "Major function" mutations carriers had 3. 7 fold increase in melanoma risk compared to subjects without R mutations. This result indicates strong genetical predisposition mediated via MC1R gene on melanoma risk in Polish population. MC1R polymorphisms evaluation may play an important role in prophylactic screening examinations. According to our results earring R151C or R160W variant allele is associated with a fourand twofold increase in skin melanoma risk; therefore detecting one of these variants using minisequencing method may be of a high diagnostic value. The quick diagnostic test prepared in this study is very sensitive, trustworthy, economical and may be used in wide prophylactic studies. We did not detect correlation between ASIP genotypes (AJA, AJG, G/G) and melanoma risk. ASIP variants did not modify correlation between MC1R variants and melanoma risk. "Major function" -R variant carriers in MC1 R gene, 3.3 times more frequently had basal cell carcinoma compared to subjects without these mutations. Eye and hair colour, skin phototype, presence of freckles or nevi did not ; modify this association. R151C variant was strongly associated with basal cell carcinoma risk. Similarly to melanoma there was no correlation between specific ASIP genotypes (AJA, AJG, G/G) and basal cell carcinoma risk. We did not observe ASIP polymorphism association with MC1 R variants in all of studied subjects. Our results indicate that ASIP and MC1 R genes act independently. Although their protein products interact on the ligant level, genotyping simultaneously both of these genes seems not to have diagnostic value.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

dermatologia ; onkologia

Degree grantor:

Wydział Lekarski

Promoter:

Wojas-Pelc, Anna

Date issued:

2007

Identifier:

oai:dl.cm-uj.krakow.pl:1158

Call number:

ZB-106061

Language:

pol

Access rights:

tylko w bibliotece

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Last modified:

Jul 19, 2022

In our library since:

Nov 21, 2012

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