BackgroundCancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.Methodology/Principal FindingsWe performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12–9.23]; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.ConclusionOur results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
Hemoglobinopathies belong to the most common monogenic hereditary diseases worldwide. A particularly high prevalence is seen in the Mediterranean countries, in parts of Asia, the Middle East and West Africa. Nevertheless, due to migration hemoglobinopathies play an increasingly important role in Germany as well. Basic testing consists of blood count and hemoglobin differentiation. In addition, an iron deficiency should be excluded if necessary. Molecular genetic testing is used for the verification of hematologic findings and serves in the assessment of risk for a severe form of a hemoglobinopathy in offspring. In order to ensure efficient diagnostics, family history and previous findings of the patient should be communicated to the laboratory. This is especially crucial in the case of prenatal diagnostics.
ZusammenfassungDer Begriff Hämoglobinopathien umfasst genetisch bedingte Krankheiten, die entweder durch die Präsenz von anomalen Hämoglobinen oder Thalassämien gekennzeichnet sind. Sie zählen zu den häufigsten Erbkrankheiten der Weltbevölkerung. Aufgrund der steigenden Migrationrate spielen Hämoglobinopathien und deren Diagnose bzw. Behandlung auch in Nord- und Mitteleuropa und ebenso in Deutschland eine wichtige Rolle. Mit 200 Mio. Betroffenen gehören die Thalassämiesyndrome, hierbei hauptsächlich α- und β-Thalassämie, weltweit zu den am häufigsten auftretenden monogenen Erkrankungen. Neben den Thalassämieerkrankungen bilden die anomalen Hämoglobine die zweite große Gruppe innerhalb der Hämoglobinopathien. In diese Gruppe fallen Hämoglobine wie HbS, HbC und HbE. In dieser Arbeit wird auf die wichtigsten Hämoglobinopathien, ihrem hämatologischen Erscheinungsbild und ihrer genetischen Ursache eingegangen. Dabei liegt der Fokus insbesondere auf der Stufendiagnostik, die bei der Abklärung solcher Erkrankungen eine entscheidende Rolle spielt.
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