title: Impaired 8-hydroxyguanine repair activity of MUTYH variant p.Arg109Trp found in a Japanese patient with early-onset colorectal cancer.
abstract: OBJECTIVE
  The biallelic inactivation of the 8-hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients.
  
  
  METHODS
  Thirty-four Japanese patients with early-onset CRC were examined for germline MUTYH and OGG1 mutations using sequencing.
  
  
  RESULTS
  Biallelic pathogenic mutations were not found in any of the patients; however, a heterozygous p.Arg19∗  MUTYH variant and a heterozygous p.Arg109Trp MUTYH variant were detected in one patient each. The p.Arg19∗ and p.Arg109Trp corresponded to p.Arg5∗ and p.Arg81Trp, respectively, in the type 2 nuclear-form protein. The defective DNA repair activity of p.Arg5∗ is apparent, while that of p.Arg81Trp has been demonstrated using DNA cleavage and supF forward mutation assays.
  
  
  CONCLUSIONS
  These results suggest that biallelic MUTYH or OGG1 pathogenic mutations are rare in Japanese patients with early-onset CRC; however, the p.Arg19∗ and p.Arg109Trp MUTYH variants are associated with functional impairments.
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Kazuya
authors.identifier: 0000-0003-4963-746X
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan ; Division of Cancer Development System, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Hong
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Hisami
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Research Center for Environmental Quality Management, Kyoto University, Shiga 520-0811, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Guang
authors.initials: G
authors.lastname: Yin
authors.affiliation: Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Suminori
authors.initials: S
authors.lastname: Kono
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Haruhiko
authors.identifier: 0000-0002-0779-3088
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human