title: HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer.
abstract: OBJECTIVE
  Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.
  
  
  METHODS
  The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.
  
  
  RESULTS
  The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10(-5) for maximum on-treatment ALT (MaxALT); P = 4.8 × 10(-4) for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10(-5) for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10(-4) for ALT > 3× ULN, P = 9.8 × 10(-3) for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10(-5) for MaxALT, P = 5.1 × 10(-6) for time to ALT > 3×ULN event, P = 5.8 × 10(-6) for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.
  
  
  CONCLUSIONS
  These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania. chun-fang.2.xu@gsk.com.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Chris
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Graves
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Liling
authors.initials: L
authors.lastname: Warren
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Xue
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Karen S
authors.initials: KS
authors.lastname: King
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Fraser
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Sandy
authors.initials: S
authors.lastname: Stinnett
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Briley
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Ionel
authors.initials: I
authors.lastname: Mitrica
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Spraggs
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Tada
authors.affiliation: Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.affiliation: Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007191:Indazoles; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D011743:Pyrimidines / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib