Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

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) x 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 x ULN. The odds ratio (95% Cl) for ALT >= 3 x ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT >= 3 x 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 pazopanib-treated patients with RCC. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.