Article: article from journal or magazin.
Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.
Journal of Hepatology
Publication types: Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC.¦METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels.¦RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure.¦CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.
Aged, Alanine Transaminase/blood, Angiogenesis Inhibitors/adverse effects, Antineoplastic Agents/adverse effects, Carcinoma, Renal Cell/drug therapy, Carcinoma, Renal Cell/enzymology, Female, Genes, MHC Class I, Genes, MHC Class II, Genetic Markers, Histocompatibility Antigens Class I/genetics, Humans, Kidney Neoplasms/drug therapy, Kidney Neoplasms/enzymology, Male, Membrane Proteins/genetics, Middle Aged, Pharmacogenetics, Polymorphism, Single Nucleotide, Pyrimidines/adverse effects, Sulfonamides/adverse effects
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