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DPD-Exon 14 Skipping mutation and 5-FU-Toxizität - DPD

Dihydropyrimidine-dehydrogenase defiziency

Clinical Features

5-Fluorouracil (5-FU) is one of the most common chemotherapeutic substances used to treat tumor diseases. The enzyme Dihydropyrimidine-Dehydrogenase (DPD) represents the first and foremost step in the resorption of 5-FU in the patient's body.

There are several genetic mutations in the DPD gene (also known as DYPD) that can lead to the loss in DPD activity. One of these mutations, commonly occurring in the general European population with a heterozygous frequency of approximately 1%, causes so-called "Exon 14 skipping" resulting in a shortened, inactive enzyme. Affected patients are unable to sufficiently break down 5-FU, which results in dangerous, often life-threatening side-effects. Various studies have shown that approximately 40% of heterozygous Exon 14 skipping mutation carriers suffer level 4 poisoning after receiving a standard dose of 5-FU. Identifying an Exon 14 skipping mutation can predict approximately 1/3 of all serious cases of 5-FU poisoning. Mutation carriers can then receive the appropriate and/or alternative treatment or receive a significantly reduced amount of 5-FU before beginning therapy.

The Consortium for Internal Oncology of the German Cancer Association strongly recommends 5-FU screening prior to the start of 5-FU chemotherapy.

Genetic Information

The DPD gene is located on chromosome 1 (1p22). To date, numerous mutations, deletions and insertions in the DPD gene have been described, most of which have no clear-cut correlation with DPD deficiency. However, approximately 40% with the mutation G>A at position +1 in intron 14 (which results in "Exon 14 skipping") experience serious, life-threatening side-effects after receiving a standard dose of 5-FU.

Prevalence

DPD Exon 14 Skipping mutations occur with a frequency of approx. 0,91 - 0,94% in the Caucasian population.

Diagnostic