Clinicopathological investigation of FLCN dysfunction and renal disorders using the immortalized cells derived from BHD-associated renal tumors.

• Project/Area Number: 17K08745
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Yokohama City University
• Principal Investigator: Furuya Mitsuko 横浜市立大学, 医学部, 准教授 (10361445)
• Co-Investigator(Kenkyū-buntansha): 田中 玲子 千葉大学, 真菌医学研究センター, 助教 (60143319)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Birt-Hogg-Dube (BHD) 症候群 / FLCN / 遺伝性腫瘍 / 腎細胞癌 / 家族性腫瘍 / 腎細胞がん / BHD症候群 / 遺伝性平滑筋腫症－腎細胞癌症候群 / HLRCC / がん関連遺伝子 / 染色体 / コピー数 / 前がん病変

Outline of Final Research Achievements

We performed clinicopathological analysis of 224 Japanese families with Birt-Hogg-Dube syndrome (BHD).
We found 10 kidney cancer families whose probands had extremely poor prognoses. They had characteristic histopathological features such as Type 2 papillary, tubulocystic and FH deficiency. They were diagnosed with Hereditary leiomyomatosis and renal cell cancer. All tumors had loss of heterozygosity of FH.
We also found 10 RBM10-TFE3 kidney cancer cases. They were positive for TFE3 but had equivocal split by dual color FISH. 10 cases included chronic renal failure-associated cancers and bilateral cancers. Further analysis is needed to clarify carcinogenesis mechanisms.

Academic Significance and Societal Importance of the Research Achievements

希少腎癌は多数例での分子病理学的解析が困難であり, これまで中々実現しなかったが, 本研究は専門医らの協力によって豊富な症例数を集約し, 独自性の高い研究を行い, 希少がん診断や治療に貢献できる研究成果として発信できた. ここ1,2年本邦においてがんパネル検査が保険診療で開始されたが,遺伝性腫瘍の殆どは二次的所見があっても患者さんに伝えることが許可されず, 保険診療では情報を十分に生かせない状態が今後も続くと予想される. 我々の研究成果は患者家族の診療に反映していかねばならない重要な知見であり, 日常診療で遭遇する「特殊な組織型」を呈する疾患にも有用な情報を提供すると見込まれる.

Research Products

• [Int'l Joint Research] Harvard Medical School(米国)
• [Journal Article] RBM 10 ‐ TFE 3 Renal Cell Carcinoma Characterized by Paracentric Inversion with Consistent Closely Split Signals in Break‐apart Fluorescence in situ Hybridization: Study of Ten Cases and a Literature Review (2019)
  • Author(s): Kato Ikuma、Furuya Mitsuko、Baba Masaya、Kameda Yoichi、Yasuda Masanori、Nishimoto Koshiro、Oyama Masafumi、Yamasaki Toshinari、Ogawa Osamu、Niino Hitoshi、Nakaigawa Noboru、Yano Yuta、Sakamoto Kazumasa、Urata Yoji、Mikami Kazuya、Yamasaki Shigetaka、Tanaka Reiko、Takagi Toshio、Kondo Tsunenori、Nagashima Yoji
  • Journal Title: Histopathology Volume: 印刷中 Issue: 2 Pages: 254-265
  • DOI: 10.1111/his.13866
  • Peer Reviewed / Open Access
• [Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • Author(s): Baba M, Furuya M, Motoshima T, Lang M, Funasaki S, Ma W, Sun HW, Hasumi H, Huang Y, Kato I, Kadomatsu T, Satou Y, Morris N, Karim BO, Ileva L, Kalen JD, Wilan Krisna LA, Hasumi Y, Sugiyama A, Kurahashi R, Nishimoto K, Oyama M, Nagashima Y, Kuroda N, Araki K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 8 Pages: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hereditary leiomyomatosis and renal cell cancer syndrome in which skin biopsy enabled diagnosis. (2019)
  • Author(s): Matsuda T, Kambe N, Ly NTM, Hatakeyama UI, Yamazaki S, Ohe C, Yoshida K, Kinoshita H, Furuya M, Okamoto H
  • Journal Title: J Dermatol Volume: 46 Issue: 8
  • DOI: 10.1111/1346-8138.14855
  • Peer Reviewed
• [Journal Article] Pathology of Birt-Hogg-Dub? syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review (2019)
  • Author(s): Furuya Mitsuko、Nakatani Yukio
  • Journal Title: Pathology International Volume: 69 Issue: 1 Pages: 1-12
  • DOI: 10.1111/pin.12752
  • Peer Reviewed
• [Journal Article] Hereditary leiomyomatosis and renal cell cancer syndrome in which skin biopsy enabled diagnosis (2019)
  • Author(s): Matsuda T, Kambe N, Ly NTM, Ueda-Hayakawa I, Yamazaki F, Ohe C, Yoshida K, Kinoshita H, Furuya M, Okamoto H
  • Journal Title: Journal of Dermatology. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] A novel partner of TFE3 in the Xp11 translocation renal cell carcinoma: clinicopathological analyses and detection of EWSR1-TFE3 fusion (2018)
  • Author(s): Fukuda Hironori、Kato Ikuma、Furuya Mitsuko、Tanaka Reiko、Takagi Toshio、Kondo Tsunenori、Nagashima Yoji
  • Journal Title: Virchows Archiv Volume: 474 Issue: 3 Pages: 389-393
  • DOI: 10.1007/s00428-018-2509-8
  • Peer Reviewed / Open Access
• [Journal Article] Medullary carcinoma of the pancreas radiologically followed up as a cystic lesion for 9?years: a case report and review of the literature (2018)
  • Author(s): Yago Akikazu、Furuya Mitsuko、Mori Ryutaro、Yabushita Yasuhiro、Sawada Yu、Kumamoto Takafumi、Matsuyama Ryusei、Shimizu Michio、Endo Itaru
  • Journal Title: Surgical Case Reports Volume: 4 Issue: 1 Pages: 80-80
  • DOI: 10.1186/s40792-018-0487-3
  • Peer Reviewed
• [Journal Article] Hereditary leiomyomatosis and renal cell cancer without cutaneous manifestations in two Japanese siblings (2018)
  • Author(s): Noguchi Go、Furuya Mitsuko、Okubo Yoichiro、Nagashima Yoji、Kato Ikuma、Matsumoto Kana、Tanaka Reiko、Hisasue Shin-ichi、Yao Masahiro、Kishida Takeshi
  • Journal Title: International Journal of Urology Volume: 25 Issue: 9 Pages: 832-835
  • DOI: 10.1111/iju.13760
  • Peer Reviewed / Open Access
• [Journal Article] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes (2018)
  • Author(s): Hasumi Hisashi、Furuya Mitsuko、Tatsuno Kenji、Aburatani Hiroyuki、Linehan W Marston、Yao Masahiro, et al.
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 15 Pages: 2712-2724
  • DOI: 10.1093/hmg/ddy181
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parotid Oncocytoma as a Manifestation of Birt-Hogg-Dub? Syndrome (2018)
  • Author(s): Yoshida Kazuki、Miyagawa Masao、Kido Teruhito、Ide Kana、Sano Yoshifumi、Sugawara Yoshifumi、Takahata Hiroyuki、Monden Nobuya、Furuya Mitsuko、Mochizuki Teruhito
  • Journal Title: Case Reports in Radiology Volume: 2018 Pages: 1-7
  • DOI: 10.1155/2018/6265175
  • Peer Reviewed
• [Journal Article] Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase (2018)
  • Author(s): Matsumoto Kana、Udaka Naoko、Hasumi Hisashi、Nakaigawa Noboru、Nagashima Yoji、Tanaka Reiko、Kato Ikuma、Yao Masahiro、Furuya Mitsuko
  • Journal Title: Pathology International Volume: 68 Issue: 8 Pages: 473-478
  • DOI: 10.1111/pin.12684
  • Peer Reviewed / Open Access
• [Journal Article] Splice-site mutation causing partial retention of intron in the FLCN gene in Birt- Hogg-Dube syndrome: a case report (2018)
  • Author(s): Furuya M, Kobayashi H, Baba M, Ito T, Tanaka R, Nakatani Y
  • Journal Title: BMC Medical Genomics Volume: 42 Issue: 1 Pages: 42-42
  • DOI: 10.1186/s12920-018-0359-5
  • Peer Reviewed / Open Access
• [Journal Article] Giant cell tumours of bone treated with denosumab: histological, immunohistochemical and H3F3A mutation analyses (2018)
  • Author(s): Kato Ikuma、Furuya Mitsuko、Matsuo Kosuke、Kawabata Yusuke、Tanaka Reiko、Ohashi Kenichi
  • Journal Title: Histopathology Volume: 72 Issue: 6 Pages: 914-922
  • DOI: 10.1111/his.13448
  • Peer Reviewed
• [Journal Article] Establishment and characterization of BHD-F59RSVT, an immortalized cell line derived from a renal cell carcinoma in a patient with Birt-Hogg-Dube syndrome (2017)
  • Author(s): Furuya M, Hasumi H, Baba M, Tanaka R, Iribe Y, Onishi T, Nagashima Y, Nakatani Y, Isono Y, Yao M.
  • Journal Title: Laboratory Investigation Volume: 97 Issue: 3 Pages: 343-351
  • DOI: 10.1038/labinvest.2016.137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation. (2017)
  • Author(s): Hasumi H, Hasumi Y, Baba M, Nishi H, Furuya M, Vocke CD, Lang M, Irie N, Esumi C, Merino MJ, Kawahara T, Isono Y, Makiyama K, Warner AC, Haines DC, Wei MH, Zbar B, Hagenau H, Feigenbaum L, Kondo K, Nakaigawa N, Yao M, Metwalli AR, Marston Linehan W, Schmidt LS
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 354-366
  • DOI: 10.1093/hmg/ddw392
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Partial Pleural Covering for Intractable Pneumothorax in Patients with Birt-Hogg-Dubé Syndrome (2017)
  • Author(s): Okada A, Hirono T, Watanabe T, Hasegawa G, Tanaka R, Furuya M
  • Journal Title: Clin Respir J Volume: 11 Issue: 2 Pages: 224-229
  • DOI: 10.1111/crj.12328
  • Peer Reviewed
• [Journal Article] Uterine carcinosarcoma-induced pulmonary tumor thrombotic microangiopathy: A case report (2017)
  • Author(s): Hibiya T, Umeda S, Okudela K, Furuya M, Yamanaka S, Ohashi K
  • Journal Title: Hum Pathol Case Reports Volume: 11 Pages: 79-82
  • Peer Reviewed
• [Journal Article] Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumor (2017)
  • Author(s): Kuroda N, Ohe C, Kato I, Furuya M, Baba M, Nagashima Y, Nakatani Y, Murakami I, Zhou M, Michal M, He O, Amin MB
  • Journal Title: Pol J Pathol Volume: 68 Issue: 4 Pages: 284-290
  • DOI: 10.5114/pjp.2017.73920
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Rare lung cystic lesions (2019)
  • Author(s): Furuya M, Nakatani Y
  • Organizer: 31st ECP
  • Int'l Joint Research / Invited
• [Presentation] Birt-Hogg-Dubé (BHD) Syndrome-Associated Lung Cysts: Histopathological Analysis and Differential Diagnosis from Miscellaneous Cystic Lung Diseases. (2019)
  • Author(s): Furuya M, Nakatani Y
  • Organizer: 31st ECP
  • Int'l Joint Research
• [Presentation] RBM10-TFE3 renal cell carcinoma characterized by paracentric inversion with consistent closely split signals in break-apart fluorescence in situ hybridization: Study of ten cases. (2019)
  • Author(s): Furuya M, Kato I, Nagashima Y, Kuroda N, Hasumi H, Baba M, Tanaka R, Yao M, Nakatani Y
  • Organizer: 31st ECP
  • Int'l Joint Research
• [Presentation] FH欠損腫瘍10例の遺伝学的, 疫学的, 臨床病理学的検討: HLRCCとの関連を含めて (2019)
  • Author(s): 古屋充子, 大江知里, 黒田直人, 長嶋洋治
  • Organizer: 第108回日本病理学会総会
• [Presentation] TFE3再構成腎細胞癌32例の臨床病理学的解析 (2019)
  • Author(s): 古屋充子, 馬場理也, 加藤生真, 矢尾正祐, 近藤恒徳, 長嶋洋治
  • Organizer: 第78回日本癌学会総会
• [Presentation] Pathologic Characteristics of the Hereditary Renal Cell Carcinomas Associated with Birt-Hogg-Dubé Syndrome (2018)
  • Author(s): Furuya M, Kato I, Nagashima Y, Kuroda N, Hasumi H, Baba M, Tanaka R, Yao M, Nakatani Y.
  • Organizer: USCAP
  • Int'l Joint Research
• [Presentation] Histopathologic Clues to the Diagnosis of Lung Cysts Associated with Birt-Hogg-Dubé Syndrome (BHDS): An analysis of 57 Cases in Comparison with Idiopathic Bullae/Blebs. (2018)
  • Author(s): Nakatani Y, Furuya M.
  • Organizer: USCAP
  • Int'l Joint Research
• [Presentation] Newly Emerging Hereditary Kidney Cancer: BHD Syndrome and Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) (2018)
  • Author(s): Furuya M, Kato I, Hasumi H, Nagashima Y, Yao M
  • Organizer: Global Academic Programs GAP 2018 conference
  • Int'l Joint Research
• [Presentation] True Neoplastic Cells in Giant Cell Tumor of Bone are Osteoblast Lineage Cells. (2018)
  • Author(s): Kato I, Furuya M, Kawabata Y, Tanaka R, Ohashi K.
  • Organizer: Global Academic Programs GAP 2018 conference
  • Int'l Joint Research
• [Presentation] Ｘ染色体短腕上でTFE3と融合遺伝子を形成するMiT family 転座型腎細胞癌の2例 (2018)
  • Author(s): 古屋充子, 加藤生真, 馬場理也, 亀田陽一, 安田政実, 西本絋嗣郎, 田中玲子,長嶋洋治
  • Organizer: 第107回日本病理学会総会
• [Presentation] Clinicopathological Analyses of 17 Cases of Xp11Translocation Renal Cell Carcinomas (2018)
  • Author(s): 古屋充子, 馬場理也, 加藤生真, 長嶋洋治, 釜井隆男, 山崎俊成, 小川修, 小山政史, 神波大己, 元島崇信, 近藤 恒徳, 江藤正俊, 長嶋洋治
  • Organizer: 第77回日本癌学会総会
• [Presentation] Genetic, epidemiologic and clinicopathologic studies of Japanese patients with Birt Hogg Dube syndrome, 2018 update (2018)
  • Author(s): 入部康弘, 矢尾正祐, 長嶋洋治, 蓮見壽史, 馬場理也,中谷行雄, 古屋充子
  • Organizer: 第77回日本癌学会総会
• [Presentation] Molecular Pathology of Renal Cell Carcinomas and Miscellaneous Neoplasms in Patients with Birt-Hogg-Dubé Syndrome (2017)
  • Author(s): Furuya M
  • Organizer: GAP 2017 Conference
  • Int'l Joint Research
• [Presentation] Clinicopathologic Analysis of Birt-Hogg-Dubé Syndrome associated Renal Cell Carcinomas (2017)
  • Author(s): Furuya M, Kato I, Nagashima Y, Hasumi H, Yao M, Baba M, Tanaka R, Nakatani Y
  • Organizer: XXIX European Congress of Pathology
  • Int'l Joint Research
• [Presentation] Birt-Hogg-Dubé症候群を背景に発症する腎腫瘍の分子病理学的特徴 (2017)
  • Author(s): 古屋充子, 加藤生真, 田中玲子, 長嶋洋治, 黒田直人, 矢尾正祐, 中谷行雄
  • Organizer: 第107回日本病理学会総会
• [Presentation] Birt-Hogg-Dubé症候群おける腎がんおよび全身臓器腫瘍の検討 (2017)
  • Author(s): 古屋充子, 中谷行雄, 蓮見寿史, 長嶋洋治, 黒田直人, 野村文夫, 馬場理也, 田中玲子, 矢尾正祐
  • Organizer: 第23回日本家族性腫瘍学会学術集会
• [Presentation] Molecular Characteristics of Renal Cell Carcinomas (RCCs) in Patients with Birt-Hogg-Dubé Syndrome (2017)
  • Author(s): 古屋充子, 蓮見壽史, 加藤生真, 馬場理也, 長嶋洋治, 入部康弘, 中谷行雄, 矢尾正祐
  • Organizer: 第76回日本癌学会総会
• [Presentation] Birt-Hogg-Dubé症候群のポストゲノム包括診療 (2017)
  • Author(s): 古屋充子
  • Organizer: 第63回日本病理学会秋期特別総会
  • Invited
• [Book] 病理と臨床 (2017)
  • Author(s): 古屋 充子
  • Total Pages: 7
  • Publisher: 文光堂
• [Remarks] Birt-Hogg-Dube 症候群情報ネット
  • URL: https://www.bhd-net.jp/
• [Remarks] 横浜市立大学医学部分子病理学講座
  • URL: http://www-user.yokohama-cu.ac.jp/~testwp/wp-admin
• [Remarks] Birt-Hogg-Dubé 症候群情報ネット
  • URL: https://www.bhd-net.jp/