Exome array analysis of adverse reactions to fluoropyrimidine-based therapy for gastrointestinal cancer.

Matthew Traylor,Monica A Hernandez,James Spicer,Anthony M Marinaki,Jemma L Walker,Christopher G Mathew,Cathryn M Lewis,Stephen J Newhouse,Hamel Patel,Amos A Folarin,Jeremy D Sanderson,Paul J Ross,Natalie J Prescott,Adele A Corrigan,Zongli Xu

doi:10.1371/journal.pone.0188911

Abstract

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers—either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful.

Highlights

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers—either as monotherapy or in combination therapy
Our dataset consisted of 504 individuals of European ancestry (Table 1) for which information was available on 74,224 SNPs, 59,277 of which were proteinaltering variants and 2,283 of which resided in the Human Leukocyte Antigen (HLA) region
We performed Combined and Multivariate Collapsing (CMC) and Sequence Kernel Association (SKAT) tests to evaluate whether genetic variation in tested genes contributed to Adverse reactions (ADRs)

Summary

Introduction

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers—either as monotherapy or in combination therapy. [2, 3] Common symptoms of toxicity include diarrhea, mucositis, and neutropenia; as well as a distinctive dermatological toxic reaction known as hand-and-foot syndrome (HFS).[4] Some degree of HFS is common (50–60%) in patients treated with the fluoropyrimidine pro-drug Capecitabine, but severe reactions are more rare, occurring in 10–17% of individuals.[4]. Variants in the dihydropyrimidine dehydrogenase (DPYD) gene, which encodes the primary enzyme required to metabolise fluororacil, contribute to risk of toxicity.[5, 6] these variants are rare, explaining only a proportion of risk, and other contributing factors are likely to exist. A genome-wide study of toxicity has been reported, but none of the identified associations have since been validated. [11] Genetic associations with HFS have been reported, [8, 12, 13] but large well-powered genetic studies of HFS are largely absent from the literature

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