Kazuo Shimozato

Aichi Gakuin University, Nagoya, Aichi, Japan

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Publications (106)156.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: There has been some debate as to whether a subset of metaplastic Warthin tumors (mWTs) harbor the mucoepidermoid carcinoma (MEC)-associated CRTC1-MAML2 fusion. We analyzed 15 tumors originally diagnosed as mWT (mWT-like tumors), 2 of which had concurrent MECs. We looked for the CRTC1/3-MAML2 fusion transcripts and performed immunohistochemistry for p63 and fluorescence in situ hybridization (FISH) for the MAML2 split. To localize MAML2 split-positive cells at the cellular level, whole tumor tissue sections were digitalized (whole-slide imaging [WSI]). The CRTC1-MAML2, but not CRTC3-MAML2 was detected in 5/15 mWT-like tumors. FISH-WSI results showed that all epithelial cells harbored the MAML2 split in fusion-positive mWT-like tumors and were totally negative in fusion-negative mWT-like tumors. A review of the hematoxylin and eosin-stained slides showed that morphology of the "metaplastic" epithelium was virtually indistinguishable between fusion-positive and fusion-negative tumors. However, oncocytic bilayered tumor epithelium, characteristic to typical WT, was always found somewhere in the fusion-negative tumors but not in the fusion-positive tumors. This distinguishing histologic finding enabled 5 pathologists to easily differentiate the 2 tumor groups with 100% accuracy. The age and sex distribution of fusion-positive mWT-like tumor cases was similar to that of fusion-positive MEC cases and significantly different from those of fusion-negative mWT-like tumor and typical WT cases. In addition, only fusion-positive mWT-like tumors possessed concurrent low-grade MECs. In conclusion, a subset of mWT-like tumors were positive for the CRTC1-MAML2 fusion and had many features that are more in accord with MEC than with WT. The term Warthin-like MEC should be considered for fusion-positive mWT-like tumors.
    The American journal of surgical pathology 10/2015; 39(11):1479-1487. DOI:10.1097/PAS.0000000000000507 · 5.15 Impact Factor

  • International Journal of Oral and Maxillofacial Surgery 10/2015; 44:e228-e229. DOI:10.1016/j.ijom.2015.08.139 · 1.57 Impact Factor
  • T. Hayakawa · H. Fukano · S. Miyabe · N. Ishii · I. Oh-iwa · T. Hashimoto · K. Shimozato ·

    International Journal of Oral and Maxillofacial Surgery 10/2015; 44:e224. DOI:10.1016/j.ijom.2015.08.124 · 1.57 Impact Factor
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    ABSTRACT: Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypopalstic and/or aplastic clavicles, midface hypoplasia, absent or delayed closure of cranial sutures, moderately short stature, delayed eruption of permanent dentition and supernumerary teeth. The molecular pathogenesis can be explained in about two-thirds of CCD patients by haploinsufficiency of the RUNX2 gene. In our current study, we identified a novel and rare variant of the RUNX2 gene (c.181_189dupGCGGCGGCT) in a Japanese patient with phenotypic features of CCD. The insertion led an alanine tripeptide expansion (+3Ala) in the polyalanine tract. To date, a RUNX2 variant with alanine decapeptide expansion (+10Ala) is the only example of a causative variant of RUNX2 with polyalanine tract expansion to be reported, whilst RUNX2 (+1Ala) has been isolated from the healthy population. Thus, precise analyses of the RUNX2 (+3Ala) variant were needed to clarify whether the tripeptide expanded RUNX2 is a second disease-causing mutant with alanine tract expansion. We therefore investigated the biochemical properties of the mutant RUNX2 (+3Ala), which contains 20 alanine residues in the polyalanine tract. When transfected in COS7 cells, RUNX2 (+3Ala) formed intracellular ubiquitinated aggregates after 24h, and exerted a dominant negative effect in vitro. At 24h after gene transfection, whereas slight reduction was observed in RUNX2 (+10Ala), all of these mutants significantly activated osteoblast-specific element-2, a cis-acting sequence in the promoter of the RUNX2 target gene osteocalcin. The aggregation growth of RUNX2 (+3Ala) was clearly lower and slower than that of RUNX2 (+10Ala). Furthermore, we investigated several other RUNX2 variants with various alanine tract lengths, and found that the threshold for aggregation may be RUNX2 (+3Ala). We conclude that RUNX2 (+3Ala) is the cause of CCD in our current case, and that the accumulation of intracellular aggregates in vitro is related to the length of the alanine tract. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Mutagenesis 07/2015; DOI:10.1093/mutage/gev057 · 2.79 Impact Factor
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    ABSTRACT: Intraosseous lymphoma in the maxilla or mandible is sometimes difficult to diagnose because of the absence of specific signs and symptoms. This study reports five cases of intraosseous lymphoma in the oral and maxillofacial regions. There were four cases of diffuse large B-cell lymphoma (DLBCL), including EBV-positive DLBCL of the elderly, and one of Burkitt's lymphoma. Regarding the tumor sites, three of the cases were in the maxilla, while two were in the mandible. Two of the conditions were clinically diagnosed as inflammatory diseases at the time of their first examination. Two patients died of their lymphoma during the follow-up period. Based on these events and findings, we clearly realized that careful examination is necessary to be diagnosed early, which results in a much better prognosis. Moreover, maxillofacial surgeons need to keep following up carefully on their patients to immediately recognize any recurrences after completion of treatment.
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    ABSTRACT: Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452-9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency.
    PLoS ONE 06/2015; 10(6):e0128227. DOI:10.1371/journal.pone.0128227 · 3.23 Impact Factor
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    ABSTRACT: Management of oral leukoplakia - a potentially malignant disorder - is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia.46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10mg/day of beta-carotene and 500mg/day of vitamin C) or placebo arm (50mg/day of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint.The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (P=0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (P=0.580) by the Cox proportional hazards model. No unfavourable side-effects were noted.Beta-carotene (10mg/day) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2015; 136(7). DOI:10.1002/ijc.29156 · 5.09 Impact Factor
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    ABSTRACT: Mammary analogue secretory carcinoma (MASC) is a recently described low-grade carcinoma with morphologic and genetic similarity, including ETV6-NTRK3 fusion, to secretory carcinoma of the breast. ETV6 is frequently involved in other epithelial and nonepithelial tumors, and many fusion partners of ETV6 have been reported. In the present study, 14 Japanese MASC cases were clinicopathologically and molecularly analyzed. The median age of the patients was 39 years, and the male:female ratio was 6:8. All cases showed histopathologic findings compatible with those previously described for MASC and harbored an ETV6 split as visualized by fluorescence in situ hybridization. Two cases showed thick fibrous septa and invasive features including vascular or perineural tumor involvement, findings that are rare in MASC. In addition, in these 2 cases, non-NTRK3 genes appeared to fuse with ETV6 (ETV6-X fusion). NTRK1 and NTRK2, both members of the NTRK family, were not involved. Of the 14 MASC cases, the ETV6-NTRK3 fusion transcript was positive in 6 cases, and the relative expression level of the ETV6-NTRK3 fusion transcript was variable, ranging from 1 to 5.8. Results of the present study of MASC suggest that (1) ETV6 occasionally fuses with unknown non-NTRK3 genes, (2) ETV6-X cases might have an invasive histology, (3) for molecular diagnosis of MASC, fluorescence in situ hybridization to detect ETV6 splits is the method of choice, and (4) the expression level of the ETV6-NTRK3 fusion transcript is considerably variable. These findings provide a novel insight into the oncogenesis, histopathology, diagnosis, treatment, and prognosis of this newly recognized carcinoma.
    American Journal of Surgical Pathology 02/2015; 39(5). DOI:10.1097/PAS.0000000000000392 · 5.15 Impact Factor
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    ABSTRACT: Androgen receptor (AR) is usually expressed in salivary duct carcinoma (SDC), but only infrequently in other carcinoma types including mucoepidermoid carcinoma (MEC). The clinicopathological characteristics of AR-positive MEC remain to be clarified. Here we report a case of AR-positive MEC. A 76-year-old man presented with a growing painless tumor of the right parotid. The resected tumor was a high-grade tumor with necroses. Since the tumor was positive for AR, GCDFP-15, and HER2, SDC was first suspected, but it was also positive for CK5/6 and P63, and negative for S-100 protein and α-smooth muscle actin. In addition, scattered mucous secreting tumor cells were found in the tumor nests, and they were positive for Alcian blue. A diagnosis of AR-positive MEC was finally made. The patient died of the tumor 5 years after the surgery. The present case may expand the histopathological spectrum of high-grade MEC. © The Author(s) 2015.
    International Journal of Surgical Pathology 01/2015; 23(3). DOI:10.1177/1066896914565024 · 0.95 Impact Factor

  • Nippon Koku Geka Gakkai zasshi 01/2015; 61(7):374-378. DOI:10.5794/jjoms.61.374
  • N. Kamiya · N. Kuroyanagi · H. Miyachi · H. Fujii · S. Yamamoto · T. Nagao · K. Shimozato ·

    Journal of Oral and Maxillofacial Surgery 09/2014; 72(9):e141-e142. DOI:10.1016/j.joms.2014.06.255 · 1.43 Impact Factor

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    ABSTRACT: Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.
    PLoS ONE 08/2014; 9(8):e102944. DOI:10.1371/journal.pone.0102944 · 3.23 Impact Factor
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    ABSTRACT: Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% (95% CI: 6.1 to 7.7%) and 0.1% (95% CI: 0.04 to 0.3%), respectively, and sibling recurrence risk of these were 24.5 (95% CI: 13.8 to 38.3%) and 43.8% (95% CI: 26.4 to 62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides.
    Clinical Genetics 07/2014; 88(2). DOI:10.1111/cge.12456 · 3.93 Impact Factor
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    ABSTRACT: Iris hypoplasia (IH) is rare autosomal dominant disorder characterized by a poorly developed iris stroma and malformations of the eyes and umbilicus. This disorder is caused by mutation of the paired-like homeodomain 2 (PITX2) gene. Here, we describe a novel PITX2 mutation (c.205C4T) in an IH family presenting with very mild eye features but with tooth agenesis as the most obvious clinical feature. Human Genome Variation (2014) 1, 14005; doi:10.1038/hgv.2014.5; published online 31 July 2014 Mutations in the PITX2 (paired-like homeodomain 2) gene are associated with three allelic disorders: iris hypoplasia (IH), iridogoniodysgenesis syndrome (IGDS; OMIM 137600) and Axenfeld-Rieger syndrome (ARS; OMIM 180500). 1–3 Various dental abnormalities including tooth agenesis are also found in IH, IGDS and ARS, which are characterized by abnormal development of the anterior segment of the eyes and umbilicus anomalies. 1–4 IH shows the mildest phenotype among the three, characterized by only iris hypoplasia and glaucoma. 1,5 IGDS presents with goniodysgenesis in addition to iris hypoplasia and glaucoma. 2
    06/2014; 1. DOI:10.1038/hgv.2014.5
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    Nippon Koku Geka Gakkai zasshi 01/2014; 60(12):677-681. DOI:10.5794/jjoms.60.677
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    ABSTRACT: The maxillofacial area is prone to the lodging of foreign objects in tissue, which are often difficult to remove. We describe a patient in whom foreign objects that were lodged deep in facial tissue were removed by using an optical navigational guidance system. An 84-year-old man presented with wounds on his face after falling through a glass door. Computed tomography images showed multiple radiopaque markers in the pterygopalatine fossa and temporal region. An optical navigation system was used to locate the foreign objects, and the glass pieces that were embedded in the skin and deeper tissues were extracted by using a guided navigation system with the patient under general anesthesia. Thus, foreign objects lodged in the maxillofacial area were successfully removed by using a guided navigation system in a minimally invasive manner.
    Nippon Koku Geka Gakkai zasshi 01/2014; 60(4):214-218. DOI:10.5794/jjoms.60.214
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    ABSTRACT: Mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease caused by various autoantibodies. This study aimed to evaluate the diagnostic value of MMP-specific autoantibodies in patient sera. We analyzed sera from 30 MMP-suspected patients with intractable oral mucosal lesions using a combination of indirect immunofluorescence with 1M NaCl-split skin, immunoblot analysis, and ELISAs. We also analyzed clinical features among different types of MMP. Seventeen, 4, and 3 patients were diagnosed with anti-BP180-type MMP, anti-laminin-332-type MMP, and combined anti-BP180/anti-laminin-332-type MMP, respectively. Our results indicated that a combination of immunologic testing for circulating autoantibodies is useful for the diagnosis of MMP.
    12/2013; 117(4). DOI:10.1016/j.oooo.2013.12.402
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    ABSTRACT: Nonsyndromic tooth agenesis is one of the most common anomalies in human development. Part of the malformation is inherited and is associated with paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) mutations. To obtain a comprehensive understanding of the genetic and molecular mechanisms that underlie this genetic disease, we investigated six familial and seven sporadic Japanese cases of nonsyndromic tooth agenesis. Searches for mutations in these candidate genes detected a novel nonsense mutation (c.416G>A) in exon 1 of MSX1 from a family with oligodontia. This mutation co-segregated in the affected family members. Moreover, this mutation produced a termination codon in the first exon and therefore the gene product (W139X) was truncated at the C terminus, hence, the entire homeodomain/MH4, which has many functions, such as DNA binding, protein-protein interaction, and nuclear localization, was absent. We characterized the properties of this truncated MSX1 by investigating the subcellular localization of the mutant gene product in transfected cells. The wild-type MSX1 localized exclusively at the nuclear periphery of transfected cells, whereas the mutant MSX1 was stable but localized diffusely throughout the whole cell. These results indicate that W139X MSX1 is responsible for tooth agenesis.
    European Journal Of Oral Sciences 12/2013; 122(1). DOI:10.1111/eos.12105 · 1.49 Impact Factor
  • M. Goto · T. Saito · H. Sato · T. Okubo · N. Kuroyanagi · H. Hachiya · K. Kurita · K. Shimozato ·

    International Journal of Oral and Maxillofacial Surgery 10/2013; 42(10):1315. DOI:10.1016/j.ijom.2013.07.493 · 1.57 Impact Factor

Publication Stats

808 Citations
156.51 Total Impact Points


  • 2003-2015
    • Aichi Gakuin University
      • • Department of Oral and Maxillofacial Surgery
      • • Department of Dentistry
      Nagoya, Aichi, Japan
  • 2012
    • Nara Medical University
      • Department of Oral and Maxillofacial Surgery
      Kashihara, Nara, Japan
  • 2006
    • Nagasaki University
      • Graduate School of Biomedical Sciences
      Nagasaki, Nagasaki, Japan