title: Association of Single Nucleotide Polymorphisms in STAT3 with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors: A Retrospective Analysis in Japanese Patients.
abstract: BACKGROUND
  Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity.
  
  
  OBJECTIVE
  Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs).
  
  
  METHODS
  Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development.
  
  
  RESULTS
  The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80-10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38-48.07; P = 0.001). In a time-to-event Kaplan-Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009).
  
  
  CONCLUSIONS
  The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. yamakz@med.kobe-u.ac.jp.
authors: Kazuhiro
authors: K
authors: Yamamoto
authors: Department of Clinical Psycho-Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan.
authors: Kazuaki
authors: K
authors: Shinomiya
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Takeshi
authors: T
authors: Ioroi
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Sachi
authors: S
authors: Hirata
authors: Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Kenichi
authors: K
authors: Harada
authors: Department of Oncology Pharmaceutical Care & Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan.
authors: Manabu
authors: M
authors: Suno
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Tatsuya
authors: T
authors: Nishioka
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Manabu
authors: M
authors: Kume
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Hiroo
authors: H
authors: Makimoto
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.|Division of Pharmacokinetics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Tsutomu
authors: T
authors: Nakagawa
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.|Division of Pharmacokinetics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Takeshi
authors: T
authors: Hirano
authors: Division of Dermatology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Toshinori
authors: T
authors: Bito
authors: Division of Dermatology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Chikako
authors: C
authors: Nishigori
authors: Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Hideaki
authors: H
authors: Miyake
authors: Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Masato
authors: M
authors: Fujisawa
authors: Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.|Division of Pharmacokinetics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Midori
authors: M
authors: Hirai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D060831:Hand-Foot Syndrome / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000235:genetics*; D012871:Skin Diseases / Q000139:chemically induced* / Q000453:epidemiology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011505:Protein-Tyrosine Kinases