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Regulatory CDH4 genetic variants associate with risk to develop capecitabine-induced hand-foot syndrome

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Fecha
20/01/2021
Autor
Ruiz Pinto, Sara
Pita, Guillermo
Martín, Miguel
Núñez Torres, Rocío
Cuadrado, Ana
Shahbazi, Marta
Caronia, Daniela
Kojic, Alexander
Moreno, Leticia
de la Torre Montero, Julio César
Lozano, María
López-Fernández, Luis Andrés
Ribelles, Nuria
García-Saénz, Jose Angel
Alba, Emilio
Milne, Roger
Losada, Ana
Pérez-Moreno, Mirna
Benítez, Javier
González-Neira, Anna
Estado
info:eu-repo/semantics/publishedVersion
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Capecitabine-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.
 
URI
https://doi.org/10.1002/cpt.2013
Regulatory CDH4 genetic variants associate with risk to develop capecitabine-induced hand-foot syndrome
Tipo de Actividad
Artículos en revistas
ISSN
0009-9236
Materias/ categorías / ODS
Bienestar, salud y sociedad
Palabras Clave
CDH4; Capecitabina; R-cadherin; síndrome mano-pie; defectos de la barrera cutánea
CDH4; Capecitabine; R-cadherin; hand-foot syndrome; skin barrier defects.
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