title: Frequent mutations in NOTCH1 ligand-binding regions in Japanese oral squamous cell carcinoma.
abstract: Recent studies showed that head and neck squamous cell carcinoma (HNSCC) including oral squamous cell carcinoma (OSCC) of Caucasian, Chinese and Indian patients frequently have NOTCH1 mutations. We found eight of 84 OSCC in Japanese patients have point mutations (9.5%) correspond to the ligand binding region of NOTCH1 protein. Two set of them are the same mutations and all mutations are non-synonymous G>A transitions. In addition, median disease-free survival is significantly longer in patients with NOTCH1-mutated tumors as compared to those without the mutation (P<0.05). The protein structure simulation based on X-ray crystallography indicated that new p.A465T mutation leads to a conformational change of NOTCH1 ligand binding domain as well as the p.G481S mutant NOTCH1 with a loss of flexibility around this residue. These results suggest that NOTCH1 mutation occurs frequently in Japanese OSCC in the vicinity of the ligand binding region and, these mutations cause downregulation of the NOTCH1 function.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan; Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Kagemasa
authors.initials: K
authors.lastname: Kajiwara
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hirayama
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Electronic address: kimura@is.icc.u-tokai.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kimura
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008958:Models, Molecular; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D011487:Protein Conformation; D051881:Receptor, Notch1 / Q000235:genetics* / Q000648:ultrastructure*; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D005819:Genetic Markers; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: Japanese oral squamous cell carcinoma; Ligand binding region; NOTCH1; Point mutation; Protein structure simulation