Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2

• Published in: Experimental dermatology Vol. 19; no. 9; pp. 836 - 844
• Main Authors: Ibarrola-Villava, Maider, Fernandez, Lara P., Pita, Guillermo, Bravo, Jerónimo, Floristan, Uxua, Sendagorta, Elena, Feito, Marta, Avilés, José A., Martin-Gonzalez, Manuel, Lázaro, Pablo, Benítez, Javier, Ribas, Gloria
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2010; Blackwell
• Subjects: 3' Untranslated Regions; Alleles; Biological and medical sciences; Case-Control Studies; Dermatology; Gene Frequency; Genes, p16; Genetic Predisposition to Disease; Genotype; Guanine Nucleotide Exchange Factors - genetics; Haplotypes; Humans; Medical sciences; melanocortin 1 receptor gene; melanoma; Melanoma - genetics; Melanoma - pathology; Membrane Transport Proteins - genetics; Multivariate Analysis; oculocutaneous albinism type II gene; Phenotype; polymorphism; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptor, Melanocortin, Type 1 - genetics; Risk Factors; Skin - pathology; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Spain; Tumors of the skin and soft tissue. Premalignant lesions; Spain; haplotypes; Dermatology; melanocortin 1 receptor gene; Malignant melanoma; melanoma; polymorphism; Malignant tumor; oculocutaneous albinism type II gene; Cancer
• ISSN: 0906-6705; 1600-0625
• DOI: 10.1111/j.1600-0625.2010.01115.x

Please cite this paper as: Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2. Experimental Dermatology 2010; 19: 836–844.
:  The CDKN2A gene is regarded as the major familial malignant melanoma (MM) susceptibility gene. Human pigmentation is one of the main modulators of individual risk of developing MM. Therefore, the genes involved in the determination of skin colour and tanning response are potentially implicated in MM predisposition and may be useful predictors of MM risk in the general population. The human melanocortin‐1 receptor gene (MC1R) plays a crucial role in pigmentation and also appears to be important in MM. The OCA2 gene has emerged as a new and significant determinant of human iris colour variation. We present a case–control study in Spanish population including 390 consecutive patients with melanoma and 254 control subjects. Sequence analysis of the entire coding region and genotyping of 5 tag‐SNPs in the genomic region of MC1R was performed. We identified 27 variants, two reaching statistical significance [R160W (OR: 4.18, 95% CI: 1.24–14.04, P = 0.02) and D294H (OR: 3.10, 95% CI: 1.37–7.01, P = 0.01)] and we detected two novel non‐synonymous changes: V92L and T308M. Odds ratio for carrying two functional variants was 4.25 (95% CI: 2.30–7.84, P = 3.63 × 10−6). Haplotypes of the entire MC1R region have been established, and we observed an enrichment of a rare European haplotype similar to African values carrying variants V92M and I155T. In addition, three potentially functional SNPs were selected in p16/CDKN2A and in the promoter region of OCA2/HERC2. Our data for CDKN2A gene did not reach statistically significant results for any of the two studied alleles. We found that the variant allele A > G of OCA2/HERC2 (rs12913832) was associated with pigmentation features: eye, hair and skin colour; P‐values = 1.8 × 10−29, 9.2 × 10−16, 1.1 × 10−3, respectively, validating previous results.