TY - JOUR

T1 - Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome

AU - Ruiz-Pinto, Sara

AU - Pita, Guillermo

AU - Martín, Miguel

AU - Nuñez-Torres, Rocío

AU - Cuadrado, Ana

AU - Shahbazi, Marta N.

AU - Caronia, Daniela

AU - Kojic, Alexander

AU - Moreno, Leticia T.

AU - de la Torre-Montero, Julio C.

AU - Lozano, María

AU - López-Fernández, Luis A.

AU - Ribelles, Nuria

AU - García-Saenz, Jose A.

AU - Alba, Emilio

AU - Milne, Roger L.

AU - Losada, Ana

AU - Pérez-Moreno, Mirna

AU - Benítez, Javier

AU - González-Neira, Anna

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1002/cpt.2013

DO - 10.1002/cpt.2013

M3 - Journal article

C2 - 32757270

AN - SCOPUS:85091039113

VL - 109

SP - 462

EP - 470

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 2

ER -