title: Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: GlaxoSmithKline Research and Development, Genetics Division, Stevenage, UK. chun-fang.2.xu@gsk.com
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Brian H
authors.initials: BH
authors.lastname: Reck
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Goodman
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Xue
authors.forename: Lingkang
authors.initials: L
authors.lastname: Huang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Barnes
authors.forename: Beena
authors.initials: B
authors.lastname: Koshy
authors.forename: Colin F
authors.initials: CF
authors.lastname: Spraggs
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Mooser
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
mesh_terms: D000368:Aged; D000410:Alanine Transaminase / Q000097:blood*; D020533:Angiogenesis Inhibitors / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D005819:Genetic Markers; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005819:Genetic Markers; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007191:Indazoles; D008565:Membrane Proteins; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000410:Alanine Transaminase