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Papers - KANAI Yae

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Development of gastric cancer-specific markers based on methylome analysis

Kameyama Shinichi, Arai Eri, Tian Ying, Ito Nanako, Shibuya Ayako, Taniguchi Hirokazu, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 430 - 430 2018.12

Joint Work, ISSN 1349-7006

Epigenomic alterations during hepatocarcinogenesis without viral, alcoholic and fatty liver injury

Makiuchi Satomi, Arai Eri, Kuramoto Junko, Tian Ying, Fukamachi Yukihiro, Takahashi Yoriko, Hiraoka Nobuyoshi, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 1304 - 1304 2018.12

Joint Work, ISSN 1349-7006

Genome-wide DNA methylation profile of young-onset endometrial cancer

Makabe Takeshi, Arai Eri, Hirasawa Akira, Yamagami Wataru, Susumu Nobuyuki, Aoki Daisuke, Kanai Yae

CANCER SCIENCE 109 1304 - 1304 2018.12

Joint Work, ISSN 1349-7006

Feasibility of methylome analysis using small amounts of genomic DNA from formalin-fixed paraffin-embedded tissue.

Ohara K, Arai E, Takahashi Y, Fukamachi Y, Ito N, Maeshima AM, Fujimoto H, Yoshida T, Kanai Y.

Pathol Int 68 ( 11 ) 633 - 635 2018.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1320-5463

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GENOME-WIDE DNA METHYLATION ANALYSIS IN YOUNG-ONSET ENDOMETRIAL CANCER

Makabe T., Arai E., Hirasawa A., Yamagami W., Nobuyuki S., Aoki D., Kanai Y.

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 28 79 - 79 2018.09

Joint Work, ISSN 1048-891X

Deleterious Pulmonary Surfactant System Gene Mutations in Lung Adenocarcinomas Associated With Usual Interstitial Pneumonia

Honda Takayuki, Sakashita Hiroyuki, Masai Kyohei, Totsuka Hirohiko, Motoi Noriko, Kobayashi Masashi, Akashi Takumi, Mimaki Sachiyo, Tsuchihara Katsuya, Chiku Suenori, Shiraishi Kouya, Shimada Yoko, Otsuka Ayaka, Kanai Yae, Okubo Kenichi, Watanabe Shun-ichi, Tsuta Koji, Inase Naohiko, Kohno Takashi

JCO PRECISION ONCOLOGY (JCO Precision Oncology) 2 1 - 24 2018.08

Joint Work

© 2019 American Society of Clinical Oncology. Purpose Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP. Patients and Methods A cohort of 691 Japanese patients with lung adenocarcinoma (LADC), of whom 54 had UIP and 637 did not, was studied for driver oncogene aberrations. Whole-exome analysis was performed for 296 cases, including 51 with UIP, to deduce mutagenic processes and identify commonly affected genes. Logistic regression analysis was used to detect associations of gene aberrations with clinicopathological factors. Results The EGFR mutation was markedly less prevalent in patients with LADC with UIP than in those without (1.9% [one of 54] v. 49.9% [318 of 637]; P <.001), even in heavy smokers (25.3% [38 of 150] of patients with > 40 pack-years; P <.001). Mutational signature analysis indicated that UIP-positive LADCs develop through accumulation of single-nucleotide and indel mutations caused by smoking. Pulmonary surfactant system genes (PSSGs) NKX2-1/TTF1, SFTPA1, SFTPA2, SFTPB, and SFTPC were identified as targets for mutations (preferentially indels), and mutations were specifically associated with shorter overall survival of patients with UIP-positive LADC, independent of pathologic stage (hazard ratio, 4.9; 95% CI, 1.7 to 14.4; P =.0037). Conclusion LADCs with UIP develop through mutational events caused by smoking, independently of EGFR mutation. PSSGs were identified as a mutational target and as a novel prognostic factor in UIP-positive LADC. PSSG deficiency might increase the malignancy of tumor cells by increasing the tumor-promoting effects of UIP.

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Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More than Continuous Exposure

Kameyama, Naofumi, Chubachi, Shotaro, Hegab, Ahmed E., Yasuda, Hiroyuki, Kagawa, Shizuko, Tsutsumi, Akihiro, Fukunaga, Koichi, Shimoda, Masayuki, Kanai, Yae, Soejima, Kenzo, Betsuyaku, Tomoko

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY (American Journal of Respiratory Cell and Molecular Biology) 59 ( 2 ) 179 - 188 2018.08

Research paper (scientific journal), Single Work, ISSN 1044-1549

Copyright © 2018 by the American Thoracic Society. Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)–induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone–induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence o

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Establishment and long-term in vitro culture of organoids derived from human biliary tract carcinomas

Saito Yoshimasa, Muramatsu Toshihide, Sugiyama Yuko, Uchida Ryoei, Furukawa Ryo, Yoshikawa Nao, Yamaguchi Tomoko, Kanai Yae, Saito Hidetsugu

CANCER RESEARCH 78 ( 13 ) 2018.07

Joint Work, ISSN 0008-5472

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A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin.

Takenouchi T, Shimada H, Uehara T, Kanai Y, Takahashi T, Kosaki K.

Eur J Med Genet (European Journal of Medical Genetics) 62 ( 2 ) 93 - 95 2018.06

Research paper (scientific journal), Single Work, Accepted, ISSN 17697212

© 2018 Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin

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Semiquantitative Evaluation of Muscle Repair by Diffusion Tensor Imaging in Mice.

Hata J, Mizuno S, Haga Y, Shimoda M, Kanai Y, Chiba K, Okano H, Nakamura M, Horiuchi K.

JBMR Plus (JBMR Plus) 2 ( 4 ) 227 - 234 2018.05

Research paper (scientific journal), Joint Work

Muscle injury is one of the most common traumas in orthopedic and sports medicine. However, there are only a few treatment options with marginal clinical benefits for this condition. Muscle repair after injury involves multiple and complex processes, such as the inflammation phase, regeneration phase, and remodeling phase. To develop a treatment modality and to examine the efficacy of novel interventions and agents for patients with muscle injuries, it is essential to establish a reliable and sensitive method to monitor the changes in muscle structure and status during muscle repair. Diffusion-weighted magnetic resonance imaging has been widely used to assess the diffusivity of water molecules in tissue. When it is used in combination with diffusion tensor imaging (DTI), the microstructure of muscle tissue can be indirectly depicted. In the present study, we evaluated the time-course changes in the diffusivity and anisotropy in muscles by DTI and histology after injury in mice. We found that the diffusivity and anisotropy exhibit distinct kinetics during muscle repair and that these kinetics were significantly altered in mutant mice with a defect in muscle regeneration. Our data show that muscle repair processes can be readily evaluated and monitored by DTI technique and suggest that DTI can be clinically applied for assessing muscle injury and repair in humans. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Novel method for DNA methylation analysis using high-performance liquid chromatography and its clinical application

Yotani, Takuya, Yamada, Yuriko, Arai, Eri, Tian, Ying, Gotoh, Masahiro, Komiyama, Motokiyo, Fujimoto, Hiroyuki, Sakamoto, Michiie, Kanai, Yae

CANCER SCIENCE (Cancer Science) 109 ( 5 ) 1690 - 1700 2018.05

Research paper (scientific journal), Single Work, ISSN 1349-7006

© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The aim of this study was to develop a new methodology that is suitable for DNA methylation diagnostics and to demonstrate its clinical applicability. We developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. The DNA methylation levels of synthetic DNA were quantified accurately and reproducibly within 10 minutes without time-consuming pretreatment of PCR products, and the measured values were unaffected by the distribution of methylated CpG within the synthetic DNA fragments. When the DNA methylation status of the FAM150A gene, a marker of the CpG island methylator phenotype specific to clear cell renal cell carcinoma (ccRCC), was examined in 98 patients with ccRCC, bulk specimens of tumorous tissue including cancer cells showing DNA methylat

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DBTSS/DBKERO for integrated analysis of transcriptional regulation

Suzuki, Ayako, Kawano, Shin, Mitsuyama, Toutai, Suyama, Mikita, Kanai, Yae, Shirahige, Katsuhiko, Sasaki, Hiroyuki, Tokunaga, Katsushi, Tsuchihara, Katsuya, Sugano, Sumio, Nakai, Kenta, Suzuki, Yutaka

NUCLEIC ACIDS RESEARCH (Nucleic Acids Research) 46 ( D1 ) D229 - D238 2018.01

Research paper (scientific journal), Single Work, ISSN 0305-1048

© 2017 The Author(s). DBTSS (Database of Transcriptional Start Sites)/DBKERO (Database of Kashiwa Encyclopedia for human genome mutations in Regulatory regions and their Omics contexts) is the database originally initiated with the information of transcriptional start sites and their upstream transcriptional regulatory regions. In recent years, we updated the database to assist users to elucidate biological relevance of the human genome variations or somatic mutations in cancers which may affect the transcriptional regulation. In this update, we facilitate interpretations of disease associated genomic variation, using the Japanese population as a model case. We enriched the genomic variation dataset consisting of the 13,368 individuals collected for various genome-wide association studies and the reference epigenome information in the surrounding regions using a total of 455 epigenome datasets (four tissue types from 67 healthy individuals) collected for the International Human Epigenome Consortium (IHEC). The data directly obtained from the clinical samples was associated with that obtained from various model systems, such as the drug perturbation datasets using cultured cancer c

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Integrated analysis of genetic and epigenetic alterations in gastric carcinomas

Yang Menghan, Arai Eri, Sakamoto Hiromi, Totsuka Hirohiko, Taniguchi Hirokazu, Katai Hitoshi, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 584 - 584 2018.01

ISSN 1349-7006

Genome-wide DNA methylation analysis in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tian Ying, Arai Eri, Kuramoto Kunko, Sukeda Aoi, Ojima Hidenori, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 238 - 238 2018.01

Joint Work, ISSN 1349-7006

Carcinogenic risk estimation based on genome-wide DNA methylation analysis during urothelial carcinogenesis

Tsumura Koji, Arai Eri, Tian Ying, Fujimoto Hiroyuki, Nakagawa Tohru, Homma Yukio, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 49 - 49 2018.01

Joint Work, ISSN 1349-7006

Formalin-fixed and paraffin-embedded tissue samples are available for genome-wide DNA methylation analysis

Ohara Kentaro, Arai Eri, Fukamachi Yukihiro, Takahashi Yoriko, Komiyama Motokiyo, Fujimoto Hiroyuki, Yoshida Teruhiko, Kanai Yae

CANCER SCIENCE 109 239 - 239 2018.01

Joint Work, ISSN 1349-7006

Genome-wide DNA methylation analysis during lung adenocarcinogenesis

Hamada Kenichi, Arai Eri, Kohno Takashi, Takahashi Yoriko, Fukamachi Yukihiro, Tsuta Koji, Watanabe Shunichi, Yoshida Teruhiko, Asamura Hisao, Kanai Yae

CANCER SCIENCE 109 239 - 239 2018.01

Joint Work, ISSN 1349-7006

The Japanese Society of Pathology Guidelines on the handling of pathological tissue samples for genomic research: Standard operating procedures based on empirical analyses.

Kanai Y, Nishihara H, Miyagi Y, Tsuruyama T, Taguchi K, Katoh H, Takeuchi T, Gotoh M, Kuramoto Y, Arai E, Ojima H, Shibuya A, Yoshida T, Akahane T, Kasajima R, Morita K, Inazawa J, Sasaki T, Fukayama M, Oda Y.

Pathol Int (Pathology International) 68 ( 2 ) 63 - 90 2018

Research paper (scientific journal), Joint Work, ISSN 13205463

© 2018 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Genome research using appropriately collected pathological tissue samples is expected to yield breakthroughs in the development of biomarkers and identification of therapeutic targets for diseases such as cancers. In this connection, the Japanese Society of Pathology (JSP) has developed “The JSP Guidelines on the Handling of Pathological Tissue Samples for Genomic Research” based on an abundance of data from empirical analyses of tissue samples collected and stored under various conditions. Tissue samples should be collected from appropriate sites within surgically resected specimens, without disturbing the features on which pathological diagnosis is based, while avoiding bleeding or necrotic foci. They should be collected as soon as possible after resection: at the latest within about 3 h of storage at 4°C. Preferably, snap-frozen samples should be stored in liquid nitrogen (about −180°C) until use. When intending to use genomic DNA extracted from formalin-fixed paraffin-embedded tissue, 10% neutral buffered formalin should be used. Insufficient fi

Epigenome mapping of human normal purified hepatocytes: personal epigenome variation and genome-epigenome correlation.

Arai E, Miura F, Totoki Y, Yamashita S, Tian Y, Gotoh M, Ojima H, Nakagawa H, Takahashi Y, Nakamura H, Hama N, Kato M, Kimura H, Suzuki Y, Ito T, Shibata T, Kanai Y.

Epigenomics (Epigenomics) 10 ( 7 ) 955 - 979 2018

Research paper (scientific journal), Single Work, ISSN 17501911

© 2018 Yae Kanai. Aim: The aim of this study was to reveal the epigenome landscape of human normal hepatocytes. Materials & methods: Cells purified from partial hepatectomy specimens of Japanese patients were subjected to whole-genome bisulfite sequencing using postbisulfite adaptor tagging, chromatin immunoprecipitation sequencing, RNA sequencing and whole-genome sequencing. Results: CHG and CHH methylations were inversely associated with gene expression. Histone modification profiles of personal differentially methylated regions (pDMRs) differed considerably among samples. pDMRs were observed around the transcription start sites of genes whose expression is reportedly regulated by CpG methylation. pDMRs were frequently observed in the vicinity of single-nucleotide variations and insertions/deletions. Conclusion: Genetic variations may induce epigenetic variations, generating individual differences in the phenotypes of normal hepatocytes through variations in expression.

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Induction of differentiation of intrahepatic cholangiocarcinoma cells to functional hepatocytes using an organoid culture system.

Saito Y, Nakaoka T, Muramatsu T, Ojima H, Sukeda A, Sugiyama Y, Uchida R, Furukawa R, Kitahara A, Sato T, Kanai Y, Saito H.

Sci Rep (Scientific Reports) 8 ( 1 ) 2821 2018

Research paper (scientific journal), Single Work, Accepted, ISSN 2045-2322

© 2018 The Author(s). Intrahepatic cholangiocarcinoma (IHCC) is a highly aggressive malignancy with a poor prognosis. It is thought to originate from cholangiocytes, which are the component cells of intrahepatic bile ducts. However, as patients with viral hepatitis often develop IHCC, it has been suggested that transformed hepatocytes may play a role in IHCC development. To investigate whether IHCC cells can be converted to functional hepatocytes, we established organoids derived from human IHCC and cultured them under conditions suitable for hepatocyte differentiation. IHCC organoids after hepatocyte differentiation acquired functions of mature hepatocytes such as albumin secretion, bile acid production and increased CYP3A4 activity. Studies using a mouse model of IHCC indicate that Wnt3a derived from macrophages recruited upon inflammation in the liver may promote the malignant transformation of hepatocytes to IHCC cells. The results of the present study support the recently proposed hypothesis that IHCC cells are derived from hepatocytes.

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