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A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

2011; Public Library of Science; Volume: 6; Issue: 4 Linguagem: Inglês

10.1371/journal.pone.0019271

1932-6203

Maider Ibarrola‐Villava, Lara P. Fernández, Santos Alonso, María Dolores Boyano, María Peña-Chilet, Guillermo Pita, José Antonio Fernández Avilés, Matías Mayor, Cristina Gómez‐Fernández, Beatriz Casado, Manuel Martín‐González, Neskuts Izagirre, Concepción de la Rúa Vaca, Aintzane Asumendi, Gorka Pérez‐Yarza, Yoana Arroyo-Berdugo, E. Boldó, Rafael Lozoya, A. Torrijos-Aguilar, A. Pitarch, Gerard Pitarch, Jose M. Sanchez-Motilla, F. Valcuende, Gloria Tomas-Cabedo, Gemma Perez-Pastor, J.L. Díaz-Pérez, Jesús Gardeazábal, Iñigo Martinez de Lizarduy, Ana Sánchez-Díez, Carlos Valdes, Ángel Pizarro, Mariano Casado, G. Carretero, Rafael Botella‐Estrada, Eduardo Nagore, Pablo Lázaro, Aña Lluch, Javier Benı́tez, Conrado Martinez‐Cadenas, Glòria Ribas,

Biochemical Analysis and Sensing Techniques

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.