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Pharmacogenet Genomics. 2014 May;24(5):231-7. doi: 10.1097/FPC.0000000000000037.

Identification of genetic variants associated with capecitabine-induced hand-foot syndrome through integration of patient and cell line genomic analyses.

Author information

1
aSection of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA bHuman Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Center cSan Carlos University Hospital dInstitute for Health Research, University Hospital Gregorio Marañón, Madrid eUniversity Hospital Virgen de la Victoria, Malaga, Spain.

Abstract

OBJECTIVE:

A primary challenge in identifying replicable pharmacogenomic markers from clinical genomewide association study (GWAS) trials in oncology is the difficulty in performing a second large clinical trial with the same drugs and dosage regimen. We sought to overcome this challenge by incorporating GWAS results from cell-based studies using the same chemotherapy as a clinical cohort.

METHODS:

In this study, we test whether the overlap between genetic variants identified in a preclinical study and a clinical study on capecitabine is more than expected by chance. A GWAS of capecitabine-induced cytotoxicity was performed in 164 lymphoblastoid cell lines derived from the CEU HapMap population and compared with a GWAS of hand-foot syndrome (HFS), the most frequent capecitabine-induced adverse drug reaction, in Spanish breast and colorectal cancer patients (n=160) treated with capecitabine.

RESULTS:

We observed an overlap of 16 single nucleotide polymorphisms associated with capecitabine-induced cytotoxicity (P<0.001) in lymphoblastoid cell lines and HFS (P<0.05) in patients, which is a greater overlap than expected by chance (genotype-phenotype permutation empirical P=0.015). Ten tag single nucleotide polymorphisms, which cover the overlap loci, were genotyped in a second patient cohort (n=85) and one of them, rs9936750, was associated with capecitabine-induced HFS (P=0.0076).

CONCLUSION:

The enrichment results imply that cellular models of capecitabine-induced cytotoxicity may capture components of the underlying polygenic architecture of related toxicities in patients.

PMID:
24595012
PMCID:
PMC4076106
DOI:
10.1097/FPC.0000000000000037
[Indexed for MEDLINE]
Free PMC Article

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