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dc.contributor.authorRuiz Pinto, Saraes-ES
dc.contributor.authorPita, Guillermoes-ES
dc.contributor.authorMartín, Migueles-ES
dc.contributor.authorNúñez Torres, Rocíoes-ES
dc.contributor.authorCuadrado, Anaes-ES
dc.contributor.authorShahbazi, Martaes-ES
dc.contributor.authorCaronia, Danielaes-ES
dc.contributor.authorKojic, Alexanderes-ES
dc.contributor.authorMoreno, Leticiaes-ES
dc.contributor.authorde la Torre Montero, Julio Césares-ES
dc.contributor.authorLozano, Maríaes-ES
dc.contributor.authorLópez-Fernández, Luis Andréses-ES
dc.contributor.authorRibelles, Nuriaes-ES
dc.contributor.authorGarcía-Saénz, Jose Angeles-ES
dc.contributor.authorAlba, Emilioes-ES
dc.contributor.authorMilne, Rogeres-ES
dc.contributor.authorLosada, Anaes-ES
dc.contributor.authorPérez-Moreno, Mirnaes-ES
dc.contributor.authorBenítez, Javieres-ES
dc.contributor.authorGonzález-Neira, Annaes-ES
dc.date.accessioned2020-08-10T09:25:51Z
dc.date.available2020-08-10T09:25:51Z
dc.date.issued20/01/2021es_ES
dc.identifier.issn0009-9236es_ES
dc.identifier.urihttps://doi.org/10.1002/cpt.2013es_ES
dc.descriptionArtículos en revistases_ES
dc.description.abstract.es-ES
dc.description.abstractCapecitabine-Induced Hand-Foot Syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of capecitabine-treated cancer patients, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in cancer patients, we carried out an extreme-phenotype genome-wide association study (GWAS) in 166 breast and colorectal capecitabine-treated cancer patients with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated SNPs associated with susceptibility to CiHFS at 20q13.33 locus (top hit=rs6129058, HR=2.40, 95%CI =1.78-3.20; P=1.2x10-8 ). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R-cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.en-GB
dc.format.mimetypeapplication/octet-streames_ES
dc.language.isoen-GBes_ES
dc.rightses_ES
dc.rights.uries_ES
dc.sourceRevista: Clinical Pharmacology and Therapeutics, Periodo: 1, Volumen: 109, Número: 2, Página inicial: 462, Página final: 470es_ES
dc.subject.otherBienestar, salud y sociedades_ES
dc.titleRegulatory CDH4 genetic variants associate with risk to develop capecitabine-induced hand-foot syndromees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.description.versioninfo:eu-repo/semantics/publishedVersiones_ES
dc.rights.holderNo open accesses_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccesses_ES
dc.keywordsCDH4; Capecitabina; R-cadherin; síndrome mano-pie; defectos de la barrera cutáneaes-ES
dc.keywordsCDH4; Capecitabine; R-cadherin; hand-foot syndrome; skin barrier defects.en-GB


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