title: A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene.
abstract: As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.
authors.affiliation: Servicio de Oncologia Medica y Hematologia, Fundacion Hospital Clinico Universitario-INCLIVA, Valencia, Spain.
authors.forename: Maider
authors.initials: M
authors.lastname: Ibarrola-Villava
authors.forename: Lara P
authors.initials: LP
authors.lastname: Fernandez
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Boyano
authors.forename: Maria
authors.initials: M
authors.lastname: Peña-Chilet
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Jose A
authors.initials: JA
authors.lastname: Aviles
authors.forename: Matias
authors.initials: M
authors.lastname: Mayor
authors.forename: Cristina
authors.initials: C
authors.lastname: Gomez-Fernandez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Casado
authors.forename: Manuel
authors.initials: M
authors.lastname: Martin-Gonzalez
authors.forename: Neskuts
authors.initials: N
authors.lastname: Izagirre
authors.forename: Concepcion
authors.initials: C
authors.lastname: De la Rua
authors.forename: Aintzane
authors.initials: A
authors.lastname: Asumendi
authors.forename: Gorka
authors.initials: G
authors.lastname: Perez-Yarza
authors.forename: Yoana
authors.initials: Y
authors.lastname: Arroyo-Berdugo
authors.forename: Enrique
authors.initials: E
authors.lastname: Boldo
authors.forename: Rafael
authors.initials: R
authors.lastname: Lozoya
authors.forename: Arantxa
authors.initials: A
authors.lastname: Torrijos-Aguilar
authors.forename: Ana
authors.initials: A
authors.lastname: Pitarch
authors.forename: Gerard
authors.initials: G
authors.lastname: Pitarch
authors.forename: Jose M
authors.initials: JM
authors.lastname: Sanchez-Motilla
authors.forename: Francisca
authors.initials: F
authors.lastname: Valcuende-Cavero
authors.forename: Gloria
authors.initials: G
authors.lastname: Tomas-Cabedo
authors.forename: Gemma
authors.initials: G
authors.lastname: Perez-Pastor
authors.forename: Jose L
authors.initials: JL
authors.lastname: Diaz-Perez
authors.forename: Jesus
authors.initials: J
authors.lastname: Gardeazabal
authors.forename: Iñigo
authors.initials: I
authors.lastname: Martinez de Lizarduy
authors.forename: Ana
authors.initials: A
authors.lastname: Sanchez-Diez
authors.forename: Carlos
authors.initials: C
authors.lastname: Valdes
authors.forename: Angel
authors.initials: A
authors.lastname: Pizarro
authors.forename: Mariano
authors.initials: M
authors.lastname: Casado
authors.forename: Gregorio
authors.initials: G
authors.lastname: Carretero
authors.forename: Rafael
authors.initials: R
authors.lastname: Botella-Estrada
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.forename: Pablo
authors.initials: P
authors.lastname: Lazaro
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.forename: Conrado
authors.initials: C
authors.lastname: Martinez-Cadenas
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013030:Spain
chemical_list: D000951:Antigens, Neoplasm; D026901:Membrane Transport Proteins; C510061:SLC45A2 protein, human