Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients.
OBJECTIVE
Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14+1G-->A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency.


METHODS
We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute.


RESULTS
Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14+1G-->A, whereas the second patient was heterozygous for a novel missense mutation 1845G-->T (E615D) in exon 14 of DPYD gene.


CONCLUSIONS
We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients.
Salgueiro
Natália
N
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
Veiga
Isabel
I
Fragoso
Maria
M
Sousa
Olga
O
Costa
Nuno
N
Pellon
Maria L
ML
Sanches
Evaristo
E
dos Santos
José Guimarães
JG
Teixeira
Manuel R
MR
Castedo
Sérgio
S
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011174:Portugal; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil