2021/10/27 更新

写真a

スダ カズアキ
須田 一暁
SUDA Kazuaki
所属
医歯学総合病院 総合周産期母子医療センター 助教
職名
助教
外部リンク

学位

  • 医学 ( 2007年3月   新潟大学 )

研究キーワード

  • 子宮内膜症

  • 子宮腺筋症

  • レーザーマイクロダイセクション

  • 子宮内膜症関連卵巣癌

  • 正常子宮内膜

  • 癌関連遺伝子

経歴(researchmap)

  • 新潟大学医歯学総合病院   Medical and Dental Hospital   特任助教

    2020年4月

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  • 新潟大学医歯学総合研究科 客員研究員

    2019年4月 - 2020年3月

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  • 新潟大学大学院医歯学総合研究科 家族性遺伝性腫瘍学講座   Graduate School of Medical and Dental Sciences   特任助教

    2016年11月 - 2019年3月

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経歴

  • 新潟大学   医歯学総合病院 総合周産期母子医療センター   特任助教

    2020年4月 - 現在

  • 新潟大学   医歯学総合研究科   特任助教

    2016年11月 - 2019年3月

学歴

  • 新潟大学医歯学総合研究科 博士課程

    2013年4月 - 2019年3月

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  • 新潟大学   医学部   医学科

    2001年4月 - 2007年3月

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  • 新潟県立長岡高等学校   理数科

    1998年4月 - 2001年3月

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所属学協会

 

論文

  • Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Koji Matsuo, Nozomi Yachida, Ai Miyoshi, Kotaro Takahashi, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kazuaki Suda, Tatsuya Ishiguro, Shujiro Okuda, Teiichi Motoyama, Hirofumi Nakaoka, Akira Kikuchi, Yutaka Ueda, Ituro Inoue, Takayuki Enomoto

    Gynecologic oncology   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear. MATERIALS AND METHODS: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status. RESULTS: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways. CONCLUSIONS: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.

    DOI: 10.1016/j.ygyno.2021.08.009

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  • The New Era of Three-Dimensional Histoarchitecture of the Human Endometrium. 国際誌

    Manako Yamaguchi, Kosuke Yoshihara, Nozomi Yachida, Kazuaki Suda, Ryo Tamura, Tatsuya Ishiguro, Takayuki Enomoto

    Journal of personalized medicine   11 ( 8 )   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The histology of the endometrium has traditionally been established by observation of two-dimensional (2D) pathological sections. However, because human endometrial glands exhibit coiling and branching morphology, it is extremely difficult to obtain an entire image of the glands by 2D observation. In recent years, the development of three-dimensional (3D) reconstruction of serial pathological sections by computer and whole-mount imaging technology using tissue clearing methods with high-resolution fluorescence microscopy has enabled us to observe the 3D histoarchitecture of tissues. As a result, 3D imaging has revealed that human endometrial glands form a plexus network in the basalis, similar to the rhizome of grass, whereas mouse uterine glands are single branched tubular glands. This review summarizes the relevant literature on the 3D structure of mouse and human endometrium and discusses the significance of the rhizome structure in the human endometrium and the expected role of understanding the 3D tissue structure in future applications to systems biology.

    DOI: 10.3390/jpm11080713

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  • Biological significance of KRAS mutant allele expression in ovarian endometriosis. 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Hiroaki Kase, Teiichi Motoyama, Takayuki Enomoto

    Cancer science   112 ( 5 )   2020 - 2032   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.

    DOI: 10.1111/cas.14871

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  • How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development. 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Manako Yamaguchi, Kazuaki Suda, Ryo Tamura, Takayuki Enomoto

    Cancers   13 ( 6 )   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as "endometriosis-associated ovarian cancer" (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC.

    DOI: 10.3390/cancers13061439

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  • Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues. 国際誌

    Haruka Ueda, Yutaro Mori, Kaoru Yamawaki, Tatsuya Ishiguro, Hirokazu Ohata, Ai Sato, Kentaro Sugino, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Ryo Tamura, Kosuke Yoshihara, Koji Okamoto, Takayuki Enomoto

    STAR protocols   2 ( 1 )   100354 - 100354   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

    DOI: 10.1016/j.xpro.2021.100354

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  • ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis 査読

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Masanori Isobe, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    Scientific Reports   10 ( 1 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

    DOI: 10.1038/s41598-020-71273-7

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    その他リンク: http://www.nature.com/articles/s41598-020-71273-7

  • Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis 査読 国際誌

    Kazuaki Suda, Luis Antonio Cruz Diaz, Kosuke Yoshihara, Hirofumi Nakaoka, Nozomi Yachida, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    Cancer Science   111 ( 8 )   3000 - 3009   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole-exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56-year-old patient. Many somatic mutations including cancer-associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele-specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.

    DOI: 10.1111/cas.14507

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14507

  • Three-dimensional understanding of the morphological complexity of the human uterine endometrium

    Manako Yamaguchi, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Nozomi Yachida, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Teiichi Motoyama, Yu Watanabe, Shujiro Okuda, Kazuki Tainaka, Takayuki Enomoto

    2020年5月

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    出版者・発行元:Cold Spring Harbor Laboratory  

    <title>Summary</title>The histological basis of the human uterine endometrium has been established by 2D observation. However, the fundamental morphology of endometrial glands is not sufficiently understood because these glands have complicated winding and branching patterns. To construct a big picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and 3D layer analyses revealed that endometrial glands formed a plexus network in the stratum basalis, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of adenomyosis, a representative “endometrium-related disease”, and observed 3D morphological features including direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, 3D analysis of the human endometrium and endometrium-related diseases will be a promising approach to better understand the pathologic physiology of the human endometrium.

    DOI: 10.1101/2020.05.29.118034

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  • XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary. 査読 国際誌

    Ryo Tamura, Kosuke Yoshihara, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Tatsuya Ishiguro, Koji Nishino, Hiroshi Ichikawa, Keiichi Homma, Akira Kikuchi, Yutaka Ueda, Yuji Takei, Hiroyuki Fujiwara, Teiichi Motoyama, Shujiro Okuda, Toshifumi Wakai, Ituro Inoue, Takayuki Enomoto

    Oncogene   39 ( 17 )   3541 - 3554   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

    DOI: 10.1038/s41388-020-1237-0

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  • Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients. 査読 国際誌

    Kentaro Sugino, Ryo Tamura, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Masanori Isobe, Masayuki Yamaguchi, Katsunori Kashima, Teiichi Motoyama, Ituro Inoue, Kosuke Yoshihara, Takayuki Enomoto

    Scientific reports   9 ( 1 )   17808 - 17808   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

    DOI: 10.1038/s41598-019-54116-y

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  • Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium. 査読 国際誌

    Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Adachi S, Kase H, Motoyama T, Inoue I, Enomoto T

    Human Reproduction   34 ( 10 )   1899 - 1905   2019年10月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    STUDY QUESTION: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium? SUMMARY ANSWER: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium. WHAT IS KNOWN ALREADY: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS). STUDY DESIGN, SIZE, DURATION: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer. MAIN RESULTS AND THE ROLE OF CHANCE: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7). LIMITATIONS, REASONS FOR CAUTION: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear. WIDER IMPLICATIONS OF THE FINDINGS: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas-Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

    DOI: 10.1093/humrep/dez155

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  • Precision medicineクリニカルシークエンスの現状と課題 HBOC診療の連携確立に向けて 新潟県の取り組み

    西野 幸治, 山口 雅幸, 安達 聡介, 吉原 弘祐, 関根 正幸, 榎本 隆之, 須田 一暁, 五十嵐 真由子, 土田 純子, 永橋 昌幸, 田澤 立之, 栗山 洋子, 藤田 沙織里, 小山 諭, 菊池 朗, 佐藤 信昭, 金子 耕司, 田村 恵美子, 三冨 亜希, 後藤 清恵

    日本婦人科腫瘍学会雑誌   37 ( 3 )   328 - 328   2019年6月

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    記述言語:日本語   出版者・発行元:(公社)日本婦人科腫瘍学会  

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  • Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report. 査読

    Suda K, Nakaoka H, Hata C, Yahata N, Isobe M, Kameyama H, Wakai T, Motoyama T, Inoue I, Yoshida K, Enomoto T

    Diagnostic Pathology   2019年2月

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    担当区分:筆頭著者  

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  • Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. 査読 国際誌

    Kazuaki Suda, Hirofumi Nakaoka, Kosuke Yoshihara, Tatsuya Ishiguro, Ryo Tamura, Yutaro Mori, Kaoru Yamawaki, Sosuke Adachi, Tomoko Takahashi, Hiroaki Kase, Kenichi Tanaka, Tadashi Yamamoto, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    Cell reports   24 ( 7 )   1777 - 1789   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

    DOI: 10.1016/j.celrep.2018.07.037

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  • 女性の家族性がん 新潟県におけるHBOC診療体制の確立に向けての取り組み

    西野 幸治, 須田 一暁, 安達 聡介, 吉原 弘祐, 関根 正幸, 榎本 隆之, 五十嵐 真由子, 土田 純子, 中島 真人, 永橋 昌幸, 田澤 立之, 栗山 洋子, 藤田 沙織里, 小山 諭, 菊池 朗, 佐藤 信昭, 金子 耕司, 田村 恵美子, 三富 亜希, 後藤 清恵

    人間ドック   33 ( 2 )   232 - 232   2018年8月

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    記述言語:日本語   出版者・発行元:(公社)日本人間ドック学会  

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  • Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. 査読 国際誌

    Ryo Tamura, Kosuke Yoshihara, Tetsuya Saito, Ryosuke Ishimura, Juan Emmanuel Martínez-Ledesma, Hu Xin, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Seiya Sato, Hiroaki Itamochi, Teiichi Motoyama, Yoichi Aoki, Shujiro Okuda, Cristine R Casingal, Hirofumi Nakaoka, Ituro Inoue, Roel G W Verhaak, Masaaki Komatsu, Takayuki Enomoto

    Oncogenesis   7 ( 1 )   4 - 4   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

    DOI: 10.1038/s41389-017-0018-2

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  • The significance of activated PI3K/AKT pathway in FGFR3-TACC3 fusion positive cervical cancer 査読

    Tamura Ryo, Yoshihara Kosuke, Saito Tetsuya, Ishimura Ryosuke, Martinez-Ledesma Emmanuel, Mori Yutaro, Yamawaki Kaoru, Suda Kazuaki, Ishiguro Tatsuya, Aoki Yoichi, Sato Seiya, Itamochi Hiroaki, Komatsu Masaaki, Verhaak Roeland, Enomoto Takayuki

    CANCER RESEARCH   77   2017年7月

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  • Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. 査読 国際誌

    Kaoru Yamawaki, Tatsuya Ishiguro, Yutaro Mori, Kosuke Yoshihara, Kazuaki Suda, Ryo Tamura, Masayuki Yamaguchi, Masayuki Sekine, Katsunori Kashima, Masaya Higuchi, Masahiro Fujii, Koji Okamoto, Takayuki Enomoto

    Cancer science   108 ( 4 )   632 - 640   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

    DOI: 10.1111/cas.13196

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  • Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer 査読

    Kaoru Yamawaki, Tatsuya Ishiguro, Yutaro Mori, Kosuke Yoshihara, Kazuaki Suda, Ryo Tamura, Masayuki Yamaguchi, Masayuki Sekine, Katsunori Kashima, Masaya Higuchi, Masahiro Fujii, Koji Okamoto, Takayuki Enomoto

    CANCER SCIENCE   108 ( 4 )   632 - 640   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions inadvanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

    DOI: 10.1111/cas.13196

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  • Biochemical analysis of intraplacental choriocarcinoma and fetomaternal transfusion 査読

    Tatsuya Ishiguro, Kazuaki Suda, Takayuki Enomoto

    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH   43 ( 3 )   587 - 591   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Intraplacental choriocarcinoma is one of the rarest forms of gestational tumors and is believed to be one of the causes of fetomaternal transfusion (FMT). A 35-year-old woman, gravida 2, para 2, with a history of two vaginal deliveries, was incidentally diagnosed as having stage I gestational intraplacental choriocarcinoma with a FIGO/World Health Organization 2000 risk score of 2 after term delivery. This disease caused neonatal anemia but did not metastasize to either the mother or infant. Short tandem repeat analysis with laser microdissection revealed that the tumor had originated from the current pregnancy. Serological test and immunohistochemical analysis revealed that the patient and her baby suffered from FMT. She has been free from disease without any medical intervention for the last 1 year. A combination of multiple biochemical analyses might help us diagnose the precursor pregnancy of a gestational choriocarcinoma and FMT.

    DOI: 10.1111/jog.13232

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  • Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma 査読

    K. Matsuo, Y. Takazawa, M. S. Ross, E. Elishaev, I. Podzielinski, M. Yunokawa, T. B. Sheridan, S. H. Bush, M. M. Klobocista, E. A. Blake, T. Takano, S. Matsuzaki, T. Baba, S. Satoh, M. Shida, T. Nishikawa, Y. Ikeda, S. Adachi, T. Yokoyama, M. Takekuma, K. Fujiwara, Y. Hazama, D. Kadogami, M. N. Moffitt, S. Takeuchi, M. Nishimura, K. Iwasaki, N. Ushioda, M. S. Johnson, M. Yoshida, A. Hakam, S. W. Li, A. M. Richmond, H. Machida, P. Mhawech-Fauceglia, Y. Ueda, K. Yoshino, K. Yamaguchi, T. Oishi, H. Kajiwara, K. Hasegawa, M. Yasuda, K. Kawana, K. Suda, T. M. Miyake, T. Moriya, Y. Yuba, T. Morgan, T. Fukagawa, A. Wakatsuki, T. Sugiyama, T. Pejovic, T. Nagano, K. Shimoya, M. Andoh, Y. Shiki, T. Enomoto, T. Sasaki, K. Fujiwara, M. Mikami, M. Shimada, I. Konishi, T. Kimura, M. D. Post, M. M. Shahzad, D. D. Im, H. Yoshida, K. Omatsu, F. R. Ueland, J. L. Kelley, R. G. Karabakhtsian, L. D. Roman

    ANNALS OF ONCOLOGY   27 ( 7 )   1257 - 1266   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Analyses of histologic patterns in 906 cases of uterine carcinosarcoma showed that both carcinoma and sarcoma components are important determinants for metastatic pattern and survival. Postoperative chemotherapy was independently protective to decrease the risk of disease progression, and there were unique associations between histologic pattern and chemotherapy response.To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma.
    A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes.
    Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P &lt; 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P &lt; 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P &lt; 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P &gt; 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P &lt; 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P &lt; 0.001).
    Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

    DOI: 10.1093/annonc/mdw161

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  • Novel kinase fusion transcripts found in endometrial cancer 査読

    Ryo Tamura, Kosuke Yoshihara, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Shujiro Okuda, Ituro Inoue, Roel G. W. Verhaak, Takayuki Enomoto

    SCIENTIFIC REPORTS   5   18657   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

    DOI: 10.1038/srep18657

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  • 初期子宮体癌に対する腹腔鏡下根治手術 複数術者によるfeasibilityと予後の検討 査読

    安達聡介, 八幡哲郎, 工藤梨沙, 山岸葉子, 山脇芳, 須田一暁, 田村亮, 茅原誠, 南川高廣, 萬歳千秋, 西野幸治, 西川伸道, 加嶋克則, 榎本隆之

    日本産科婦人科内視鏡学会雑誌   2013年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.5180/jsgoe.29.313

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