The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study.

Authors:
Francesco Iachetta
Francesco Iachetta
University of Modena and Reggio Emilia
Italy
Alessandra Romagnani
Alessandra Romagnani
Laboratory of Translational Research
Raffaella Zamponi
Raffaella Zamponi
European Institute of Oncology
Italy
Lorenzo Tofani
Lorenzo Tofani
University of Florence
Italy
Enrico Farnetti
Enrico Farnetti
Laboratory of Molecular Biology
Davide Nicoli
Davide Nicoli
University Hospital of Parma
Italy

Br J Cancer 2019 Apr 12;120(8):834-839. Epub 2019 Mar 12.

Medical Oncology Unit, Clinical Cancer Centre, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Background: Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.

Methods: In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A.

Results: From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities.

Conclusions: The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.

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http://dx.doi.org/10.1038/s41416-019-0423-8DOI Listing
April 2019
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