Discrepancies between dihydropyrimidine dehydrogenase phenotyping and genotyping: What are the explanatory factors?

AIM: Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil [U], with U ≥ 16 µg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors. METHODS: Data from patients who underwent both phenotyping and genotyping were retrospectively collected. Complementary genetic analyses (genotyping of the variant c.557A>G and DPYD sequencing) were performed for patients with U ≥ 16 µg/L without any common variants. The characteristics of patients classified according to the congruence of the phenotyping and genotyping approaches were compared (Kruskal-Wallis test), and determinants of U levels were studied in the whole cohort (linear model). RESULTS: Among the 712 included patients, phenotyping and genotyping were discordant for 12.5%, with 63 (8.8%) having U ≥ 16 µg/L in the absence of a common variant. Complementary genetic investigations marginally reduced the percentage of discrepancies to 12.1%: Among the nine additional identified variants, only the c.557A>G variant, carried by three patients, had been previously reported to be associated with DPD deficiency. Liver dysfunction could explain certain discordances, as ASAT, ALP, GGT and bilirubin levels were significantly elevated, with more frequent liver metastases in patients with U ≥ 16 µg/L and the absence of a DPYD variant. The impact of cytolysis was confirmed, as ASAT levels were independently associated with increased U (p < 0.001). CONCLUSION: The frequent discordances between DPD phenotyping and genotyping approaches highlight the need to perform these two approaches to screen for all DPD deficiencies.

[How to predict the relapse after surgery or radiofrequency of liver metastases of colorectal cancer? Interest of the serum kinetic variation of a matrix metalloproteinase cluster]. / Cinétique de variation sérique des métalloprotéïnases matricielles (MMP-1, -2, -7 et -9) et de TIMP-1 : un facteur prédictif de récidive après traitement radical des métastases hépatiques de cancers colorectaux ?

INTRODUCTION: Recurrence after liver surgery or radiofrequency is a clinical and biological challenge because it worsens the colorectal cancer prognosis. To date, no biomarker is yet validated to predict the recurrence in order to intensify adjuvant therapy for patients with higher risk. Matrix metalloproteinases play a major role in the metastasis dissemination and tumoral microenvironment and could be a potential biomarker of interest. METHODS: Forty-four patients with liver metastasis treated by surgery or radiofrequency were enrolled in this study. Serum levels of MMP-1, MMP-2, MMP-7, MMP-9 and TIMP-1 were monitored in Elisa after therapy and correlated to the recurrence from January 2004 to December 2007. After the curative treatment, patients were assessed for the recurence for two years by CT-scan and examination. RESULTS: Post-operative serum level of MMP-9 was significantly higher between J0, J1 and J45 after liver surgery or radiofrequency (***P≤0.001). Level of MMP-2 was significantly increased at M3 and M6 (***P≤0.001) but does not appear to be a risk factor of liver recurrence. The level of TIMP-1 at J0 is a deleterious factor (HR=1.76, P=0.042*). CONCLUSION: This is the first study wich correlates the post-operative level of 4 MMPs and TIMP-1 with the risk of liver recurrence after surgery or radiofrequency. Serum TIMP-1 level at J0 could be helpful to identify patients with higher risk but these results need to be confirmed in a large-scale study.