DPYD IVS14+1G>A and 2846A>T Genotyping for the Prediction of Severe Fluoropyrimidine-Related Toxicity: A Meta-Analysis

Abstract

Aim: In the present study we conducted a systematic review and meta-analysis of published data to quantify the impact of the DPYD IVS14+1G>A and 2846A>T variants on the risk of fluoropyrimidine-related toxicities and to determine sensitivity and specificity testing for DPYD variants. Methods: Relevant studies were identified through PubMed and Web of Knowledge databases, studies included were those published up until to May 2012. Study quality was assessed according to the HuGENET guidelines and Strengthening the Reporting of Genetic Association (STREGA) recommendations. Results: Random-effects meta-analysis provided evidence that carriers of DPYD IVS14+1G>A are at higher risk of ≥3 degrees of overall grade toxicity, hematological toxicity, mucositis and diarrhea. In addition, a strong association was also found between carriers of the DPYD 2846T allele and overall grade ≥3 toxicity or grade ≥3 diarrhea. An inverse linear relationship was found in prospective studies between the odds ratio of DPYD IVS14+1G>A and the incidence of overall grade ≥3 toxicity, indicating an higher impact in cohorts in which the incidence of severe toxicity was lower. Conclusion: The results of this meta-analysis confirm clinical validity of DPYD IVS14+1G>A and 2846A>T as risk factors for the development of severe toxicities following fluoropyrimidine treatment. Furthermore, the sensitivity and specificity estimates obtained could be useful in establishing the cost–effectiveness of testing for DPYD variants.

Original submitted 4 March 2013; Revision submitted 17 June 2013

KEYWORDS::

• DPYD
• fluoropyrimidines
• meta-analysis
• pharmacogenetics
• risk factors
• toxicity

Acknowledgements

The authors acknowledge B Gallo and M Bassotto for their invaluable bibliographic support.

Financial & competing interests disclosure

Financial support for this work was provided by a research grant from AIRC (Italian Association for Cancer Research)and ITT (Tuscany Tumor Institute) to R Danesi. S Cargnin is a PhD student of the Scuola di Alta Formazione, which is supported by the Compagnia di San Paolo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Financial support for this work was provided by a research grant from AIRC (Italian Association for Cancer Research)and ITT (Tuscany Tumor Institute) to R Danesi. S Cargnin is a PhD student of the Scuola di Alta Formazione, which is supported by the Compagnia di San Paolo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.