Volume 109, Issue 2 p. 462-470
Article

Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome

Sara Ruiz-Pinto

Sara Ruiz-Pinto

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

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Guillermo Pita

Guillermo Pita

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

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Miguel Martín

Miguel Martín

Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain

These authors contributed equally to this work.

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Rocío Nuñez-Torres

Rocío Nuñez-Torres

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

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Ana Cuadrado

Ana Cuadrado

Chromosome Dynamics Group. Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

These authors contributed equally to this work.

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Marta N. Shahbazi

Marta N. Shahbazi

Epithelial Cell Biology Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

These authors contributed equally to this work.

These authors contributed equally to this work.

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Daniela Caronia

Daniela Caronia

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

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Alexander Kojic

Alexander Kojic

Chromosome Dynamics Group. Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

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Leticia T. Moreno

Leticia T. Moreno

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

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Julio C. de la Torre-Montero

Julio C. de la Torre-Montero

San Juan de Dios School of Nursing and Physical Therapy, Comillas Pontifical University, Madrid, Spain

Medical Oncology Service, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain

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María Lozano

María Lozano

Laboratory and Research Divison, Taper, Madrid, Spain

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Luis A. López-Fernández

Luis A. López-Fernández

Pharmacy Department, Laboratory of Pharmacogenomics, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain

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Nuria Ribelles

Nuria Ribelles

UGC Oncología Intercentros, Institute of Biomedical Research in Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Malaga, Spain

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Jose A. García-Saenz

Jose A. García-Saenz

Medical Oncology Service, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain

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Emilio Alba

Emilio Alba

UGC Oncología Intercentros, Institute of Biomedical Research in Malaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Malaga, Spain

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Roger L. Milne

Roger L. Milne

Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia

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Ana Losada

Ana Losada

Chromosome Dynamics Group. Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

These authors contributed equally to this work.

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Mirna Pérez-Moreno

Mirna Pérez-Moreno

Epithelial Cell Biology Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

These authors contributed equally to this work.

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Javier Benítez

Javier Benítez

Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

These authors contributed equally to this work.

These authors contributed equally to this work.

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Anna González-Neira

Corresponding Author

Anna González-Neira

Human Genotyping Unit–Centro Nacional de Genotipado (CEGEN), Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Correspondence: Anna González-Neira ([email protected])

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First published: 05 August 2020
Citations: 5

These authors contributed equally to this work.

These authors contributed equally to this work.

Abstract

Capecitabine-induced hand-foot syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of patients with capecitabine-treated cancer, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in patients with cancer, we carried out an extreme-phenotype genomewide association study in 166 patients with breast and colorectal capecitabine-treated cancer with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated single-nucleotide polymorphisms associated with susceptibility to CiHFS at 20q13.33 locus (top hit = rs6129058, hazard ratio = 2.40, 95% confidence interval = 1.78–3.20; P = 1.2 × 10−8). 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.

Conflict of Interest

All authors declared no competing interests for this work.