title: Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2.
abstract: 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 x 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 x 10(-29), 9.2 x 10(-16), 1.1 x 10(-3), respectively, validating previous results.
authors.affiliation: Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Maider
authors.initials: M
authors.lastname: Ibarrola-Villava
authors.forename: Lara P
authors.initials: LP
authors.lastname: Fernandez
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Bravo
authors.forename: Uxua
authors.initials: U
authors.lastname: Floristan
authors.forename: Elena
authors.initials: E
authors.lastname: Sendagorta
authors.forename: Marta
authors.initials: M
authors.lastname: Feito
authors.forename: José A
authors.initials: JA
authors.lastname: Avilés
authors.forename: Manuel
authors.initials: M
authors.lastname: Martin-Gonzalez
authors.forename: Pablo
authors.initials: P
authors.lastname: Lázaro
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
mesh_terms: D020413:3' Untranslated Regions; D000483:Alleles; D016022:Case-Control Studies; D005787:Gene Frequency; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics*; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012307:Risk Factors; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013030:Spain; D044767:Ubiquitin-Protein Ligases
chemical_list: D020413:3' Untranslated Regions; D020662:Guanine Nucleotide Exchange Factors; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; D044102:Receptor, Melanocortin, Type 1; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases