title: Involvement of ANXA5 and ILKAP in susceptibility to malignant melanoma.
abstract: Single nucleotide-polymorphisms (SNPs) are a source of diversity among human population, which may be responsible for the different individual susceptibility to diseases and/or response to drugs, among other phenotypic traits. Several low penetrance susceptibility genes associated with malignant melanoma (MM) have been described, including genes related to pigmentation, DNA damage repair and oxidative stress pathways. In the present work, we conducted a candidate gene association study based on proteins and genes whose expression we had detected altered in melanoma cell lines as compared to normal melanocytes. The result was the selection of 88 loci and 384 SNPs, of which 314 fulfilled our quality criteria for a case-control association study. The SNP rs6854854 in ANXA5 was statistically significant after conservative Bonferroni correction when 464 melanoma patients and 400 controls were analyzed in a discovery Phase I. However, this finding could not be replicated in the validation phase, perhaps because the minor allele frequency of SNP rs6854854 varies depending on the geographical region considered. Additionally, a second SNP (rs6431588) located on ILKAP was found to be associated with melanoma after considering a combined set of 1,883 MM cases and 1,358 disease-free controls. The OR was 1.29 (95% CI 1.12-1.48; p-value = 4×10-4). Both SNPs, rs6854854 in ANXA5 and rs6431588 in ILKAP, show population structure, which, assuming that the Spanish population is not significantly structured, suggests a role of these loci on a specific genetic adaptation to different environmental conditions. Furthermore, the biological relevance of these genes in MM is supported by in vitro experiments, which show a decrease in the transcription levels of ANXA5 and ILKAP in melanoma cells compared to normal melanocytes.
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: Yoana
authors.initials: Y
authors.lastname: Arroyo-Berdugo
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Department of Hematology and Medical Oncology, Instituto Investigación Sanitaria, INCLIVA, Valencia, Spain.
authors.forename: Gloría
authors.initials: G
authors.lastname: Ribas
authors.affiliation: Department of Hematology and Medical Oncology, Instituto Investigación Sanitaria, INCLIVA, Valencia, Spain.
authors.forename: Maider
authors.initials: M
authors.lastname: Ibarrola-Villava
authors.affiliation: Department of Hematology and Medical Oncology, Instituto Investigación Sanitaria, INCLIVA, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Peña-Chilet
authors.affiliation: Department of Medicine, University of Castellon Jaume I, Castellon, Spain.
authors.forename: Conrado
authors.initials: C
authors.lastname: Martínez-Cadenas
authors.affiliation: Department of Dermatology, Ophthalmology and Otorhinolaryngology, UPV/EHU, Service of Dermatology, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo, Bizkaia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gardeazabal
authors.affiliation: Department of Dermatology, Ophthalmology and Otorhinolaryngology, UPV/EHU, Service of Dermatology, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo, Bizkaia, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Ratón-Nieto
authors.affiliation: Department of Dermatology, Ophthalmology and Otorhinolaryngology, UPV/EHU, Service of Dermatology, BioCruces Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez-Díez
authors.affiliation: Department of Dermatology, Ophthalmology and Otorhinolaryngology, UPV/EHU, Service of Dermatology, BioCruces Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain.
authors.forename: Jesús María
authors.initials: JM
authors.lastname: Careaga
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Pérez-Yarza
authors.affiliation: Department of Dermatology, Doctor Negrin Hospital, Las Palmas de Gran Canaria, Spain.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Carretero
authors.affiliation: Department of Dermatology, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Martín-González
authors.affiliation: Deparment of Dermatology, La Paz University Hospital, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gómez-Fernández
authors.affiliation: Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: Aintzane
authors.initials: A
authors.lastname: Asumendi
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Boyano
mesh_terms: D017304:Annexin A5 / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D017304:Annexin A5; C426826:ILKAP protein, human; D010749:Phosphoprotein Phosphatases
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