DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis.
OBJECTIVE
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.


CONCLUSIONS
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.
Dipartimento di Scienze del Farmaco & Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica-CRIFF, Università del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100 Novara, Italy. terrazzino@pharm.unipmn.it
Salvatore
S
Terrazzino
Sarah
S
Cargnin
Marzia
M
Del Re
Romano
R
Danesi
Pier Luigi
PL
Canonico
Armando A
AA
Genazzani
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics* / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation
D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil