Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.
Data(s) |
2011
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Resumo |
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. |
Identificador |
http://serval.unil.ch/?id=serval:BIB_88E2F3B51D6F isbn:0168-8278 (Print) pmid:21145803 doi:10.1016/j.jhep.2010.09.028 isiid:000291523000022 |
Idioma(s) |
en |
Fonte |
Journal of Hepatology, vol. 54, no. 6, pp. 1237-1243 |
Palavras-Chave | #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 |
Tipo |
info:eu-repo/semantics/article article |