title: Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.
abstract: BACKGROUND
  Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse.
  
  
  METHODS
  We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively.
  
  
  RESULTS
  UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.
  
  
  CONCLUSIONS
  These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. mafu0218@yahoo.co.jp.|Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. mafu0218@yahoo.co.jp.
authors.forename: Aki
authors.initials: A
authors.lastname: Mafune
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. takanori@jikei.ac.jp.|Department of Oto-Rhino-laryngology, Jikei University School of Medicine, 3 - 25 - 8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. takanori@jikei.ac.jp.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hama
authors.affiliation: Department of Oto-Rhino-laryngology, Jikei University School of Medicine, 3 - 25 - 8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. tssuda@jikei.ac.jp.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Surgery, International University of Health and welfare, Tochigi, Japan. yutaka@iuhw.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Jikei University School of Medicine, Tokyo, Japan. ikegami@jikei.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikegami
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. c.sakanashi@gmail.com.
authors.forename: Chikako
authors.initials: C
authors.lastname: Sakanashi
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. h22ms-imai@jikei.ac.jp.
authors.forename: Satoko
authors.initials: S
authors.lastname: Imai
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. a-nakashima@jikei.ac.jp.|Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. a-nakashima@jikei.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Nakashima
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. tyokoo@jikei.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoo
authors.affiliation: Department of Oto-Rhino-laryngology, Jikei University School of Medicine, 3 - 25 - 8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. k.wada@mbd.ocn.ne.jp.|Department of Otorhinolaryngology, Toho University, Tokyo, Japan. k.wada@mbd.ocn.ne.jp.
authors.forename: Kota
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Oto-Rhino-laryngology, Jikei University School of Medicine, 3 - 25 - 8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. kojimah@jikei.ac.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. urashima@jikei.ac.jp.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Urashima
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D012008:Recurrence; D017384:Sequence Deletion; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015778:Minor Histocompatibility Antigens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human