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

• Published in: Journal of hepatology Vol. 54; no. 6; pp. 1237 - 1243
• Main Authors: Xu, Chun-Fang, Reck, Brian H, Goodman, Vicki L, Xue, Zhengyu, Huang, Lingkang, Barnes, Michael R, Koshy, Beena, Spraggs, Colin F, Mooser, Vincent E, Cardon, Lon R, Pandite, Lini N
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.06.2011; Elsevier
• Subjects: Aged; Alanine aminotransferase; Alanine Transaminase - blood; Angiogenesis Inhibitors - adverse effects; Antineoplastic Agents - adverse effects; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - enzymology; Carcinoma, Renal Cell - genetics; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Genes, MHC Class I; Genes, MHC Class II; Genetic Markers; GW786034; Hemochromatosis Protein; Hepatotoxicity; HFE; Histocompatibility Antigens Class I - genetics; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - enzymology; Kidney Neoplasms - genetics; Kidneys; Male; Medical sciences; Membrane Proteins - genetics; Metabolic diseases; Metals (hemochromatosis...); Middle Aged; Nephrology. Urinary tract diseases; Other metabolic disorders; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrimidines - adverse effects; Sulfonamides - adverse effects; Tumors of the urinary system; drug-induced liver injury; CC; DILI; Pharmacogenetics; quantitative trait analysis; CI; HFE; alanine aminotransferase; ALT; upper limit of the normal range; human leukocytic antigen; renal cell carcinoma; RCC; ULN; GW786034; VEGFR; vascular endothelial growth factor receptor; confidence interval; case–control; HLA; Hepatotoxicity; QTA; Alanine aminotransferase; Antineoplastic agent; Carcinoma; Toxicity; Hepatic disease; Iron; Enzymopathy; Gastroenterology; Genetics; Grawitz tumor; Protein-tyrosine kinase; Pazopanib; Kidney disease; Iron overload; Urinary system disease; Hemochromatosis; Enzyme; Tyrosine kinase inhibitor; Transferases; Metabolic diseases; Malignant tumor; Transaminases; Alanine transaminase; Digestive diseases; Cancer
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2010.09.028

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 (r2 = 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.