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ABSTRACT: Since the international gastric cancer linkage consortium first proposed screening criteria for the detection of CDH1 germline mutations in hereditary diffuse gastric cancer(HDGC), the low yields of previous attempts to identify patients with HDGC in Japan, where gastric cancer is endemic and mass screenings for it have been established, have made clinicians less enthusiastic about pursuing the genetic etiology of the peculiar occurrence of gastric cancer. A report published in 2011 described a case with a typical truncated mutation of CDH1 and another with an exon 3 deletion of this gene. These findings have rekindled the curiosity of practicians and pathologists confronted with unusual gastric cancers of various types such as younger- onset, familial clustering, or the exhibition of a specific characteristic morphology. The status and history of the investigation of the genetic backgrounds of Japanese gastric cancers are reviewed, and the pathological features of the Japanese cases of HDGC are described.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2013; 40(2):154-8.
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ABSTRACT: To investigate the suppressive activity of MUTYH variant proteins against mutations caused by oxidative lesion, 8-hydroxyguanine (8OHG), in human cells.
p.R154H, p.M255V, p.L360P, and p.P377L MUTYH variants, which were previously found in patients with colorectal polyposis and cancer, were selected for use in this study. Human H1299 cancer cell lines inducibly expressing wild-type (WT) MUTYH (type 2) or one of the 4 above-mentioned MUTYH variants were established using the piggyBac transposon vector system, enabling the genomic integration of the transposon sequence for MUTYH expression. MUTYH expression was examined after cumate induction using Western blotting analysis and immunofluorescence analysis. The intracellular localization of MUTYH variants tagged with FLAG was also immunofluorescently examined. Next, the mutation frequency in the supF of the shuttle plasmid pMY189 containing a single 8OHG residue at position 159 of the supF was compared between empty vector cells and cells expressing WT MUTYH or one of the 4 MUTYH variants using a supF forward mutation assay.
The successful establishment of human cell lines inducibly expressing WT MUTYH or one of the 4 MUTYH variants was concluded based on the detection of MUTYH expression in these cell lines after treatment with cumate. All of the MUTYH variants and WT MUTYH were localized in the nucleus, and nuclear localization was also observed for FLAG-tagged MUTYH. The mutation frequency of supF was 2.2 × 10(-2) in the 8OHG-containing pMY189 plasmid and 2.5 × 10(-4) in WT pMY189 in empty vector cells, which was an 86-fold increase with the introduction of 8OHG. The mutation frequency (4.7 × 10(-3)) of supF in the 8OHG-containing pMY189 plasmid in cells overexpressing WT MUTYH was significantly lower than in the empty vector cells (P < 0.01). However, the mutation frequencies of the supF in the 8OHG-containing pMY189 plasmid in cells overexpressing the p.R154H, p.M255V, p.L360P, or p.P377L MUTYH variant were 1.84 × 10(-2), 1.55 × 10(-2), 1.91 × 10(-2), and 1.96 × 10(-2), respectively, meaning that no significant difference was observed in the mutation frequency between the empty vector cells and cells overexpressing MUTYH mutants.
The suppressive activities of p.R154H, p.M255V, p.L360P, and p.P377L MUTYH variants against mutations caused by 8OHG are thought to be severely impaired in human cells.
World Journal of Gastroenterology 12/2012; 18(47):6935-42. · 2.47 Impact Factor
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Shinichiro Kiyose,
Hisaki Igarashi,
Kiyoko Nagura,
Takaharu Kamo,
Kazunori Kawane,
Hiroki Mori,
Takachika Ozawa,
Matsuyoshi Maeda,
Keisuke Konno,
Hideaki Hoshino,
Hiroyuki Konno,
Hiroyuki Ogura, Kazuya Shinmura,
Naohiko Hattori,
Haruhiko Sugimura
[show abstract]
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ABSTRACT: The chromogenic in situ hybridization (CISH) assay, designed to detect the amplification of the HER2 gene in formalin-fixed, paraffin-embedded (FFPE) breast cancer (BC) and gastric cancer (GC) tissue specimens, was evaluated in 125 FFPE BC cases and 198 FFPE GC cases for which the HER2 status had been predetermined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In the 125 BC cases and the 198 gastric cases, we found a very good concordance (98.4% and 99.0%, respectively) between CISH and FISH. In particular, we evaluated the polysomy cases, as these cases often have ambiguous treatment options in clinical practice. The polysomy of chromosome 17 was defined as the presence of three or more CEP17 signals in at least 10% of the tumor cells. In the 50 BC cases and 54 GC cases displaying chromosome 17 polysomy, the concordance between FISH and CISH was 98.0% and 98.1%, respectively. These results indicate that CISH could provide an accurate and practical alternative to FISH for the clinical diagnosis of HER2 gene amplification in FFPE BC and FFPE GC samples.
Pathology International 11/2012; 62(11):728-34. · 1.62 Impact Factor
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Tomonari Matsuda,
Hong Tao,
Masanori Goto,
Hidetaka Yamada,
Masaya Suzuki,
Yijia Wu,
Nong Xiao,
Qiong He,
Wenwen Guo,
Zhenming Cai,
Nobuya Kurabe,
Keiko Ishino,
Yoshitaka Matsushima, Kazuya Shinmura,
Hiroyuki Konno,
Masato Maekawa,
Yaping Wang,
Haruhiko Sugimura
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ABSTRACT: DNA adducts are a major cause of DNA mutation and DNA mutation-related diseases, but the simultaneous identification of multiple DNA adducts has been a challenge for a decade. An adductome approach using consecutive liquid chromatography and double mass spectrometry after micrococcal nuclease treatment has paved the way to demonstrations of numerous DNA adducts in a single experiment and is expected to contribute to the comprehensive understanding of overall environmental and endogenous exposures to possible mutagens in individuals. In this report we applied an adductome approach to gastric mucosa samples taken at the time of a gastrectomy for gastric cancer in Lujiang, China, and in Hamamatsu, Japan. Seven lipid peroxidation-related DNA adducts (1,N6-etheno-2'-deoxyadenosine [εdA], butanone-etheno-2'-deoxycytidine [BεdC], butanone-etheno-2'-deoxy-5-methylcytidine [BεmedC], butanone- etheno-2'-deoxyadenosine [BεdA], heptanone-etheno-2'-deoxycytidine [HεdC], heptanone-etheno-2'-deoxyadenosine [HεdA], and heptanone-etheno- 2'-deoxyguanosine [HεεdG]) were identified in a total of 22 gastric mucosa samples. The levels of these adducts ranged from 0 to 30,000 per 10(9)bases. Although the presence of Helicobacter pylori DNA in the mucosa was not related to these adducts level, the levels of BεdC,BεdA, and HεdA were higher in the Japanese gastric mucosa samples. The profiles of these 7 adduct levels among the 21 cases were capable of discriminating between the possible origins (China or Japan) of the gastric mucosa samples. Our report is the first demonstration of lipid peroxidation-related DNA adducts in the human stomach, and the present observations warrant further investigation in the context of the significance of DNA adducts in human gastric carcinogenesis.
Carcinogenesis 10/2012; · 5.70 Impact Factor
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Shin-ichiro Kiyose,
Kiyoko Nagura,
Hong Tao,
Hisaki Igarashi,
Hidetaka Yamada,
Masanori Goto,
Matsuyoshi Maeda,
Nobuya Kurabe,
Masaya Suzuki,
Masaru Tsuboi,
Tomoaki Kahyo, Kazuya Shinmura,
Naohiko Hattori,
Haruhiko Sugimura
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ABSTRACT: To test the feasibility of using bacterial artificial chromosomes (BAC) containing kinases for pathological diagnosis using fluorescence in situ hybridization (FISH), 10 BAC probes containing a gene amplified in 5% or more of a pilot cohort were selected from a previous survey using arbitrarily selected BAC clones harboring 100 kinases. In this report, we describe the prevalence and association with the clinicopathological profile of these selected 10 BAC probes in 365 gastric cancer tissues. FISH analyses using these 10 BAC probes containing loci encoding EGFR, ERBB2(HER2), EPHB3, PIK3CA, MET, PTK7, ACK1, STK15, SRC, and HCK showed detectable amplifications in paraffin-embedded tissue in 2.83% to 13.6% of the gastric cancer tissues. Considerable numbers of the cases showed the co-amplification of two or more of the probes that were tested. BAC probes located within a genome neighborhood, such as PIK3CA, EPHB3, and ACK1 at 3q26-29 or HCK, SRC, and STK15 at 20q11-13.1, were often co-amplified in the same cases, but non-random co-amplifications of genes at distant genomic loci were also observed. These findings provide basic information regarding the creation of a strategy for personalizing gastric cancer therapy, especially when using multiple kinase inhibitors.
Pathology International 05/2012; 62(7):477-84. · 1.62 Impact Factor
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Hiroko Natsume, Kazuya Shinmura,
Hong Tao,
Hisaki Igarashi,
Masaya Suzuki,
Kiyoko Nagura,
Masanori Goto,
Hidetaka Yamada,
Matsuyoshi Maeda,
Hiroyuki Konno,
Satoki Nakamura,
Haruhiko Sugimura
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ABSTRACT: Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer.
A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide.
These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.
Journal of Translational Medicine 05/2012; 10:97. · 3.41 Impact Factor
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Elakeche Ella,
Naomi Sato,
Daisuke Nishizawa,
Shinji Kageyama,
Hidetaka Yamada,
Nobuya Kurabe,
Keiko Ishino,
Hong Tao,
Fumihiko Tanioka,
Akiko Nozawa,
Chen Renyin, Kazuya Shinmura,
Kazutaka Ikeda,
Haruhiko Sugimura
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ABSTRACT: The dopaminergic brain pathway is involved in many addictive behaviours, hence represents a good candidate in the study of smoking behaviour and nicotine addiction. Dopamine beta hydroxylase (DBH) is an enzyme that catalyses the conversion of dopamine into noradrenaline. This study, the first of its kind, was done to investigate the role of DBH rs5320 polymorphism in smoking behaviour of elderly Japanese. This was done by collecting blood samples from 2521 subjects with various smoking habits to genotype the DBH rs5320 polymorphism. Participants also had to fill out a questionnaire containing questions regarding their lifestyles. Some of the questions were from the Fagerström Test for Nicotine Dependence (FTND) and the Tobacco Dependence Screener (TDS). It was found that male ever-smokers with AA genotype smoked less cigarettes per day than those with GG and AG genotypes. FTND scores were also lowest in male ever-smokers with AA genotype and in female ever-smokers with AG genotype. There was no correlation detected between the TDS scores and any of the genotypes. This study shows that DBH rs5320 polymorphism influences nicotine dependence.
Journal of Human Genetics 04/2012; 57(6):385-90. · 2.57 Impact Factor
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ABSTRACT: Genetic polymorphisms associated with structural changes of their gene product are important in terms of their potential relation
with diseases. Therefore, in this study, splice-site variants of the transmembrane serine protease geneTMPRSS4, nephronophthisis geneNPHP4, and organic-cation transporter geneORCTL4, were selected from the dbSNP single nucleotide polymorphism database as candidates to identify genetic polymorphisms associated
with a structural change in their mRNA transcripts. The allele frequencies of theTMPRSS4 c.4-7A>G,NPHP4 c.2818-2A>T, andORCTL4 c.517-2A>C polymorphisms in a Japanese population were determined to be 0.42, 0.10, and 0.27, respectively, by PCR-SSCP analysis.
Next, the effect of these polymorphisms on the mode of pre-mRNA splicing was investigated by RT-PCR analysis followed by sequencing
analysis. TheTMPRSS4, NPHP4, andORCTL4 polymorphisms were associated with the production of the r.4-6_4-1ins transcript, the r.2818_2823del and r.2818_2859del transcripts,
and the r.517-94_517-1ins; r.517-2a>c and r.517_620del transcripts, respectively. Since the proteins encoded by all these
transcripts are associated with relatively significant structural changes in the form amino acid insertion/deletion and premature
termination, their functional ability may be greatly reduced. Our demonstration of structural changes in mRNA transcripts
as a result of splice-site polymorphisms implies that they may be of biological significance in certain pathological conditions.
Journal of Genetics 04/2012; 84(2):131-136. · 1.09 Impact Factor
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03/2012; , ISBN: 978-953-51-0180-2
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Hidetaka Yamada, Kazuya Shinmura,
Hiroaki Ito,
Masako Kasami,
Naomi Sasaki,
Hideyuki Shima,
Masami Ikeda,
Hong Tao,
Masanori Goto,
Takachika Ozawa,
Toshihiro Tsuneyoshi,
Fumihiko Tanioka,
Haruhiko Sugimura
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ABSTRACT: Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC.
Cancer Science 07/2011; 102(10):1782-8. · 3.33 Impact Factor
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Kazuya Shinmura,
Masanori Goto,
Masaya Suzuki,
Hong Tao,
Hidetaka Yamada,
Hisaki Igarashi,
Shun Matsuura,
Matsuyoshi Maeda,
Hiroyuki Konno,
Tomonari Matsuda,
Haruhiko Sugimura
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ABSTRACT: The MUTYH gene encodes a DNA glycosylase that can initiate the excision repair of adenine mispaired with 8-hydroxyguanine (8OHG) and is responsible for a susceptibility to multiple colorectal adenomas and carcinomas. To determine whether the MUTYH gene is involved in gastric carcinogenesis, we first examined the expression level of MUTYH in gastric cancer. The reduced expression of MUTYH mRNA transcript was detected in both gastric cancer cell lines and primary gastric cancers using qRT-PCR analysis. Immunohistochemical analysis also showed a significant reduction in MUTYH protein expression in gastric cancer, compared with non-cancerous gastric epithelium (immunohistochemical score, 175.5 ± 43.0 versus 281.5 ± 24.8; p < 0.0001). Among the gastric cancers, the MUTYH expression level was significantly associated with the histopathology (p < 0.0001) and the pT stage (p < 0.001). The outcome of patients with gastric cancer exhibiting low MUTYH expression was significantly worse than the outcome of patients with gastric cancer exhibiting high MUTYH expression (p = 0.0007, log-rank test) and a multivariate analysis revealed that reduced MUTYH expression was an independent predictor of a poor survival outcome among the gastric cancer patients (hazard ratio, 1.865; 95% confidence interval, 1.028-3.529; p = 0.0401). We next compared the functional effects of MUTYH on gastric cancer cells, based on their MUTYH expression levels. MUTYH-over-expressing stable clones of the gastric cancer cell line AGS showed: (a) higher DNA cleavage activity towards adenine:8OHG mispair-containing substrates; (b) higher suppressive activity against mutations caused by 8OHG in a supF forward mutation assay; and (c) higher suppressive activity for cellular proliferation than empty vector-transfected AGS clones. These results suggested that MUTYH is a suppressor of mutations caused by 8OHG in gastric cells and that its reduced expression is associated with a poor prognosis in gastric cancer.
The Journal of Pathology 06/2011; 225(3):414-23. · 6.32 Impact Factor
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Kazuya Shinmura,
Hisaki Igarashi,
Masanori Goto,
Hong Tao,
Hidetaka Yamada,
Shun Matsuura,
Mari Tajima,
Tomonari Matsuda,
Arito Yamane,
Kazuhito Funai,
Masayuki Tanahashi,
Hiroshi Niwa,
Hiroshi Ogawa,
Haruhiko Sugimura
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ABSTRACT: Activation-induced cytidine deaminase (AID) is expressed in B lymphocytes and triggers antibody diversification. Recent reports have indicated that the constitutive expression of AID in mice causes not only lymphomas, but also cancers of some organs including the lung, prompting us to investigate the expression and effect of AID on human lung cancer.
We examined AID mRNA expression in 17 lung cancer cell lines and 51 primary lung cancers using a quantitative RT-PCR analysis. Next, we established H1299 lung cancer cells stably overexpressing AID and performed a supF forward mutation assay. We then examined AID protein expression and p53 mutation in 129 primary lung cancers by an immunohistochemical analysis and PCR-SSCP and sequencing analyses, respectively.
Aberrant mRNA expression of AID was detected in 29% (5 of 17) of the lung cancer cell lines and 31% (16 of 51) of the primary lung cancers. AID-overexpressing H1299 clones showed a 5.0- to 6.1-fold higher mutation frequency than an empty vector-transfected H1299 clone, and about half of the AID-induced mutations were base substitutions, indicating that AID induces gene mutations in lung cancer cells. Furthermore, an association was found between the AID protein expression level and the p53 mutation status in an analysis of 129 primary lung cancers. A further expression analysis revealed that a portion of AID is localized at the centrosomes.
Our current findings suggest that the aberrant expression of AID may be involved in a subset of human lung cancers as a result of its mutation-inducing activity.
Annals of Surgical Oncology 02/2011; 18(7):2084-92. · 4.17 Impact Factor
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Haruhiko Sugimura,
Hong Tao,
Masaya Suzuki,
Hiroki Mori,
Masaru Tsuboi,
Shun Matsuura,
Masanori Goto, Kazuya Shinmura,
Takachika Ozawa,
Fumihiko Tanioka,
Naomi Sato,
Yoshitaka Matsushima,
Shinji Kageyama,
Kazuhito Funai,
Pei-Hsin Chou,
Tomonari Matsuda
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ABSTRACT: Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies.
Frontiers in bioscience (Scholar edition) 01/2011; 3:1463-77.
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Haruhiko Sugimura,
Jian-Dong Wang,
Hiroki Mori,
Masaru Tsuboi,
Kiyoko Nagura,
Hisaki Igarashi,
Hong Tao,
Ritsuko Nakamura,
Hiroko Natsume,
Tomoaki Kahyo, Kazuya Shinmura,
Hiroyuki Konno,
Yasushi Hamaya,
Shigeru Kanaoka,
Hideki Kataoka,
Xiao-Jun Zhou
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ABSTRACT: Ever since its discovery two decades ago, the erythropoietin-producing hepatoma (EPH)-EPHRIN system has been shown to play multifaceted roles in human gastroenterological cancer as well as neurodevelopment. Over-expression, amplification and point mutations have been found in many human cancers and many investigators have shown correlations between these up-regulations and tumor angiogenesis. Thus, the genes in this family are considered to be potential targets of cancer therapy. On the other hand, the down-regulation of some members as a result of epigenetic changes has also been reported in some cancers. Furthermore, the correlation between altered expressions and clinical prognosis seems to be inconclusive. A huge amount of protein-protein interaction studies on the EPH-EPHRIN system have provided a basic scheme for signal transductions, especially bi-directional signaling involving EPH-ERPHRIN molecules at the cell membrane. This information also provides a manipulative strategy for harnessing the actions of these molecules. In this review, we summarize the known alterations of EPH-EPHRIN genes in human tumors of the esophagus, stomach, colorectum, liver and pancreas and present the perspective that the EPH-EPHRIN system could be a potential target of cancer therapy.
World journal of gastrointestinal oncology. 12/2010; 2(12):421-8.
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ABSTRACT: Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired with 8-hydroxyguanine.
Human Mutation 11/2010; 31(11):E1861-74. · 5.69 Impact Factor
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Hong Tao, Kazuya Shinmura,
Hidetaka Yamada,
Masato Maekawa,
Satoshi Osawa,
Yasuhiro Takayanagi,
Kazuya Okamoto,
Tomohiro Terai,
Hiroki Mori,
Toshio Nakamura,
Haruhiko Sugimura
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ABSTRACT: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps and frequent extracolonic manifestations. An attenuated form of FAP (AFAP) is diagnosed based on a milder colorectal phenotype, and the colorectal phenotype of (A)FAP has been linked to germline APC mutations. The relationships between the spectrum of mutations and extracolonic manifestations are quite well known, but they need to be further defined.
Nine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.
Nine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.
BMC Research Notes 11/2010; 3:305.
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Naomi Sato,
Shinji Kageyama,
Renyin Chen,
Masaya Suzuki,
Hiroki Mori,
Fumihiko Tanioka,
Hidetaka Yamada,
Takaharu Kamo,
Hong Tao, Kazuya Shinmura,
Akiko Nozawa,
Haruhiko Sugimura
[show abstract]
[hide abstract]
ABSTRACT: Molecular heterogeneity of neuropeptide Y (NPY) and its three receptors (1, 2 and 5) has recently been discovered. NPY2R polymorphisms have been shown to be related to cocaine and alcohol dependence in European Americans. To test our hypothesis that these polymorphisms influence the smoking behavior of Japanese population, we investigated the prevalence of the rs4425326 and rs6857715 polymorphisms, which have been suggested to be related to alcohol dependence in European Americans, in 2517 Japanese elderly subjects for whom information on smoking behaviors was available. The prevalence of current smokers was greater among Japanese men having the rs4425326 C allele than ex-smokers. Among the ever-smokers, the Fagerström Test for Nicotine Dependence scores were higher in men having the rs4425326 homozygous T allelotype, and the numbers of cigarettes smoked per day were also significantly higher in the male smokers having the TT genotype. No correlations between the Tobacco Dependence Screener scores and any genotypes were detected. These results suggest that rs4425326 polymorphism may be related to smoking behavior in the Japanese elderly population. This study for the first time suggests NPY2R genotype as a possible genetic factor in nicotine dependence.
Journal of Human Genetics 11/2010; 55(11):755-60. · 2.57 Impact Factor
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Pei-Hsin Chou,
Shinji Kageyama,
Shun Matsuda,
Keishi Kanemoto,
Yoshiaki Sasada,
Megumi Oka, Kazuya Shinmura,
Hiroki Mori,
Kazuaki Kawai,
Hiroshi Kasai,
Haruhiko Sugimura,
Tomonari Matsuda
[show abstract]
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ABSTRACT: DNA adducts are produced both exogenously and endogenously via exposure to various DNA-damaging agents. Two lipid peroxidation (LPO) products, 4-oxo-2(E)-nonenal (4-ONE) and 4-oxo-2(E)-hexenal (4-OHE), induce substituted etheno-DNA adducts in cells and chemically treated animals, but the adduct levels in humans have never been reported. It is important to investigate the occurrence of 4-ONE- and 4-OHE-derived DNA adducts in humans to further understand their potential impact on human health. In this study, we conducted DNA adductome analysis of several human specimens of pulmonary DNA as well as various LPO-induced DNA adducts in 68 human autopsy tissues, including colon, heart, kidney, liver, lung, pancreas, small intestine, and spleen, by liquid chromatography tandem mass spectrometry. In the adductome analysis, DNA adducts derived from 4-ONE and 4-OHE, namely, heptanone-etheno-2'-deoxycytidine (HεdC), heptanone-etheno-2'-deoxyadenosine (HεdA), and butanone-etheno-2'-deoxycytidine (BεdC), were identified as major adducts in one human pulmonary DNA. Quantitative analysis revealed 4-ONE-derived HεdC, HεdA, and heptanone-etheno-2'-deoxyguanosine (HεdG) to be ubiquitous in various human tissues at median values of 10, 15, and 8.6 adducts per 10(8) bases, respectively. More importantly, an extremely high level (more than 100 per 10(8) bases) of these DNA adducts was observed in several cases. The level of 4-OHE-derived BεdC was highly correlated with that of HεdC (R(2) = 0.94), although BεdC was present at about a 7-fold lower concentration than HεdC. These results suggest that 4-ONE- and 4-OHE-derived DNA adducts are likely to be significant DNA adducts in human tissues, with potential for deleterious effects on human health.
Chemical Research in Toxicology 09/2010; 23(9):1442-8. · 3.78 Impact Factor
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Haruhiko Sugimura,
Hiroki Mori,
Kiyoko Nagura,
Shin-Ichiro Kiyose,
Hong Tao,
Tao Hong,
Masaru Isozaki,
Hisaki Igarashi, Kazuya Shinmura,
Akio Hasegawa,
Yasuhiko Kitayama,
Fumihiko Tanioka
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ABSTRACT: Practicing pathologists expect major somatic genetic changes in cancers, because the morphological deviations in the cancers they diagnose are so great that the somatic genetic changes to direct these phenotypes of tumors are supposed to be correspondingly tremendous. Several lines of evidence, especially lines generated by high-throughput genomic sequencing and genome-wide analyses of cancer DNAs are verifying their preoccupations. This article reviews a comprehensive morphological approach to pathology archives that consists of fluorescence in situ hybridization with bacterial artificial chromosome (BAC) probes and screening with tissue microarrays to detect structural changes in chromosomes (copy number alterations and rearrangements) in specimens of human solid tumors. The potential of this approach in the attempt to provide individually tailored medical practice, especially in terms of cancer therapy, is discussed.
Pathology International 08/2010; 60(8):543-50. · 1.62 Impact Factor
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Psychiatric genetics 04/2010; 20(3):135-6. · 2.33 Impact Factor
