June 2015 Vol. 3 No. 6

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Original Research Article

The use of 5-FU pharmacogenomics from paraffin blocks in patients with breast cancer receiving fluorouracil therapy

Libor Stanek^1,2,3, Vocka Michal³, Musil Zdenek^4,5, Petruzelka Lubos³, Jedkova Petra⁴, Kohoutova Milada⁴, Springer Drahomíra⁶ and Assoc. Prof. Tesarova Petra³*
 

¹Institute of Pathology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague,
Studnickova 2, Prague 2, 128 00, Czech Republic
²Departmen of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University in Prague, Karlovarska 48,
Pilsen, 301 66, Czech Republic
³Department of Oncology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague,
U Nemocnice 2, Prague 2, 128 08, Czech Republic
⁴Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital
in Prague, Albertov 4 , Prague 2, 128 00, Czech Republic
⁵Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol,
V Uvalu 84, Prague 5, 150 06, Czech Republic
⁶Institute ofMedicalbiochemistry and LaboratoryDiagnostics, FirstFacultyofMedicine, Charles University in Prague and General
University Hospital in Prague, U Nemocnice 2, Prague 2, 128 08, Czech Republic

*Correspondence Author’s E-mail: petra.tesarova@vfn.cz
Tel.: +420224966750

Accepted June 02, 2015

Abstract

The pyrimidine analog 5-fuorouracil (5-FU) is a cytostatic drug that is widely used for the treatment of many solid carcinomas including breast cancer. More than 80 – 85% of administered 5-FU is quickly metabolized in the liver through a series of metabolic steps involving an enzyme dihydropirimidine dehydrogenase (DPD). Patients with low DPD activity (approximately 2-4% of population) cannot effectively inactivate 5-FU which leads to high and sometimes even lethal toxicity. DPD is encoded by the DPYD gene. The mutant allele DPYD*2a is caused by a congenital mutation in the splicing sequence of intron 14 (IVS14+1G>A) of the DPYD gene. Patients with the IVS14+1G>A mutation produce a non-functional enzyme DPD and, when treated with 5-FU, toxic metabolites are accumulated in their bodies and it may lead to severe toxic reactions. Detection of the IVS14+1G>A mutation should be considered the important factor of toxicity prediction prior to the beginnig of 5-FU therapy. In our study the IVS14+1G>A mutation was detected using the certified kit PGX-5FU StripAssay (ViennaLab Diagnostics), which combines in vitro PCR and reversible hybridization. DNA was isolatated from paraffin blocks, not from blood, which accelerated the whole process of diagnostic analysis. 40 female patients with histologically verified breast cancer (Grade I.-III.), who were treated in the Department of Oncology, (First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague), participated in this pilot study. DPYD genotyping was performed in all patients. One patient was a carrier of the IVS14+1G>A mutation in a heterozygous state and no patient was a carrier of homozygous mutation. On the basis of molecular analysis and symptom-atology the heterozygous patient received only a minimum effective dose of 5-FU.

Keywords: 5-Fluorouracil, Breast carcinoma, DPYD, FFPET, Pharmacogenomics, Toxicity