title: Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients.
abstract: OBJECTIVE
  The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients.
  
  
  METHODS
  A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ (2) test.
  
  
  RESULTS
  Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type.
  
  
  CONCLUSIONS
  Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups.
authors.affiliation: Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.forename: Hyung Soon
authors.initials: HS
authors.lastname: Park
authors.forename: Woo Sun
authors.initials: WS
authors.lastname: Kwon
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Lim
authors.forename: Hyo Song
authors.initials: HS
authors.lastname: Kim
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Shin
authors.forename: Jung Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D056910:Republic of Korea; D000077210:Sunitinib
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D000077210:Sunitinib