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2023 Fiscal Year Annual Research Report

Molecular mechanisms for development of pulmonary invasive mucinous adenocarcinoma

Research Project

Project/Area Number 23H02698
Allocation TypeSingle-year Grants
Research InstitutionNational Cancer Center Japan

Principal Investigator

谷田部 恭  国立研究開発法人国立がん研究センター, 中央病院, 科長 (90280809)

Co-Investigator(Kenkyū-buntansha) 小林 祥久  国立研究開発法人国立がん研究センター, 研究所, 研究員 (30734628)
加島 淳平  国立研究開発法人国立がん研究センター, 中央病院, 医員 (80893883)
岸川 さつき  国立研究開発法人国立がん研究センター, 中央病院, 医員 (10906598)
Project Period (FY) 2023-04-01 – 2026-03-31
Keywords肺腺癌 / KRAS変異 / 浸潤性粘液腺癌 / 喫煙者肺腺癌 / アイソフォーム
Outline of Annual Research Achievements

KRAS陽性肺腫瘍は、KRAS-AAH、非喫煙者末梢型KRAS肺癌、喫煙関連KRAS腺癌、浸潤性粘液腺癌などに大別することができる。また、KRAS変異は生物学的にcellular senescenceとoncogenicの逆説的な役割を有することが知られており、臓器・細胞の特性やKRAS変異バリアント、KRAS変異isoformsの発現割合などによってその生物学的役割が異なることが報告されている。そこで本研究では、肺癌におけるKRAS変異の生物学的意義について検討を試みる。KRAS変異を有する肺腺癌179例を全エクソーム解析、トランスクリプトーム解析を行い、その分子生物学的、臨床病理学的に違いがあるか検討した。その結果、 14例の非喫煙者末梢型KRAS肺癌、95例の喫煙関連KRAS腺癌、49例の浸潤性粘液腺癌、3例の喫煙関連KRAS扁平上皮癌、その他の18例に大別することができた。unsupervised hierarchical clusteringで喫煙者KRAS肺癌と浸潤性粘液腺癌では異なるクラスターを形成するほか、KRAS変異バリアントの分布も異なり、KRASアイソフォームの発現量に違いが見られた。これら解析の中で浸潤性粘液性腺癌の一部では、突然未分化癌に転化し、明瞭な結節を形成する現象が少数ながらも見いだされ、その生物学的意義について解析し、同一クローンによる腫瘍の脱分化現象であることを報告した。さらに、肺組織のマスター制御因子であるTTF-1変異は浸潤性粘液性腺癌で特異的に見いだされ、その空間トランスクリプトームを行っている。また、解剖学的特徴とそれに関連する発生機序から見た非小細胞肺癌全体の中での浸潤性粘液腺癌の位置づけや特殊性を分子生物学的にレビューし、国際病理学会の英国機関誌に発表した。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

KRAS変異を有する肺腺癌179例を全エクソーム解析、トランスクリプトーム解析を行い、そのunsupervised hierarchical clusteringで喫煙者KRAS肺癌と浸潤性粘液腺癌では異なるクラスターを形成することが明らかになった。現在では公開されているTCGAデータを合わせて、アイソフォームの発現パターンの解析によっても検証されていることを確認している。これら結果をまとめ、雑誌投稿中である。また、浸潤性粘液腺癌におけるTTF-1の変異についてはframeshift insertion/deletion, structural variation deletion, nonsense mutationsが多くの症例で検出されており、その発現低下を裏付ける結果が得られている。これら解析の中で浸潤性粘液性腺癌の一部では、突然未分化癌に転化し、明瞭な結節を形成する現象が少数ながらも見いだされ、そのクローン性も含めてそのメカニズムや生物学的意義について解析た結果については、「粘液結節を伴う浸潤性粘液腺癌」として英文誌に発表した。さらに、解剖学的特徴とそれに関連する発生機序から見た非小細胞肺癌全体の中での浸潤性粘液腺癌の位置づけや特殊性を分子生物学的にレビューし、国際病理学会の英国機関誌に発表した。

Strategy for Future Research Activity

これまでは浸潤性粘液腺癌にKRAS変異が多いことに着目し、に検討を行ってきた。その結果、その特徴を示すことができたが、その結果に加えてもう一つの特徴である浸潤性粘液腺癌におけるTTF-1の変異について検討を進めていきたい。通常型腺癌においてはTTF-1が遺伝子増幅を示し、高悪性度や転移能と相関することをすることをこれまでの解析で示してきた。しかしながら、浸潤性粘液腺癌では機能喪失変異を来すという点で特徴的であり、両者の違いを示すことで浸潤性粘液腺癌の特徴を追求していきたい。具体的には、通常型腺癌から浸潤性粘液腺癌への移行を示す腺癌を取り上げ、その変異の腫瘍内における分布や発現パターンの変化について空間トランスクリプトームを用いて検討を進めていきたい。

  • Research Products

    (45 results)

All 2024 2023

All Journal Article (39 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 38 results,  Open Access: 6 results) Presentation (6 results)

  • [Journal Article] Molecular pathology of non-small cell carcinoma2024

    • Author(s)
      Yatabe Y.
    • Journal Title

      Histopathology

      Volume: 84 Pages: 50-66

    • DOI

      10.1111/his.15080

    • Peer Reviewed / Open Access
  • [Journal Article] Rare but clinically important salivary gland-type tumor of the lung: A review2024

    • Author(s)
      Takamori S., Yatabe Y., Osoegawa A., Aokage K., Yoshioka H., Miyoshi T., ...Watanabe S. I.
    • Journal Title

      Jpn J Clin Oncol

      Volume: 54 Pages: 121-128

    • DOI

      10.1093/jjco/hyad154

    • Peer Reviewed
  • [Journal Article] Optimizing tissue stewardship in non-small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists2024

    • Author(s)
      Kerr K. M., Bubendorf L., Lopez-Rios F., Khalil F., Roy-Chowdhuri S., Joubert P., ...Dacic S.
    • Journal Title

      Histopathology

      Volume: 84 Pages: 429-439

    • DOI

      10.1111/his.15078

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impact of (18)F-FDG PET on TNM Staging and Prognosis in Thymic Epithelial Tumors2024

    • Author(s)
      Akamine T., Nakagawa K., Ito K., Watanabe H., Yotsukura M., Yoshida Y., ...Watanabe S. I.
    • Journal Title

      Ann Surg Oncol

      Volume: 31 Pages: 192-200

    • DOI

      10.1245/s10434-023-14328-z

    • Peer Reviewed
  • [Journal Article] Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses2024

    • Author(s)
      Shiraishi K., Takahashi A., Momozawa Y., Daigo Y., Kaneko S., Kawaguchi T., ...Kohno T.
    • Journal Title

      Cancer Commun (Lond)

      Volume: 44 Pages: 287-293

    • DOI

      10.1002/cac2.12498

    • Peer Reviewed
  • [Journal Article] Inflammatory Rhabdomyoblastic Tumor: Clinicopathologic and Molecular Analysis of 13 Cases2024

    • Author(s)
      Odate T., Satomi K., Kubo T., Matsushita Y., Ueno T., Kurose A., ...Yoshida A.
    • Journal Title

      Mod Pathol

      Volume: 37 Pages: 100359

    • DOI

      10.1016/j.modpat.2023.100359

    • Peer Reviewed
  • [Journal Article] Myxoid liposarcoma with nuclear pleomorphism: a clinicopathological and molecular study2024

    • Author(s)
      Kojima N., Kubo T., Mori T., Satomi K., Matsushita Y., Iwata S., ...Yoshida A.
    • Journal Title

      Virchows Arch

      Volume: 484 Pages: 71-81

    • DOI

      10.1007/s00428-023-03631-5

    • Peer Reviewed
  • [Journal Article] Long-Term Prognosis and Prognostic Indicators of Stage IA Lung Adenocarcinoma2023

    • Author(s)
      Yotsukura M., Muraoka Y., Yoshida Y., Nakagawa K., Shiraishi K., Kohno T., ...Watanabe S. I.
    • Journal Title

      Ann Surg Oncol

      Volume: 30 Pages: 851-858

    • DOI

      10.1245/s10434-022-12621-x

    • Peer Reviewed
  • [Journal Article] The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan2023

    • Author(s)
      Yoshida T., Yatabe Y., Kato K., Ishii G., Hamada A., Mano H., ...Kohno T.
    • Journal Title

      Cancer Biol Med

      Volume: 21 Pages: 29-44

    • DOI

      10.20892/j.issn.2095-3941.2023.0036

    • Peer Reviewed
  • [Journal Article] Comments on the Article by Miura et al.: Comparable Clinical Benefit Between Different Subsets Selected by PD-L1 22C3 and SP142 Tests""2023

    • Author(s)
      Yatabe Y.
    • Journal Title

      JTO Clin Res Rep

      Volume: 4 Pages: 100492

    • DOI

      10.1016/j.jtocrr.2023.100492

    • Peer Reviewed
  • [Journal Article] Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2-IA3 EGFR-Mutated NSCLC: ADAURA22023

    • Author(s)
      Tsutani Y., Goldman J. W., Dacic S., Yatabe Y., Majem M., Huang X., ...He J.
    • Journal Title

      Clin Lung Cancer

      Volume: 24 Pages: 376-380

    • DOI

      10.1016/j.cllc.2023.02.002

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Defining Morphologic Features of Invasion in Pulmonary Nonmucinous Adenocarcinoma With Lepidic Growth: A Proposal by the International Association for the Study of Lung Cancer Pathology Committee2023

    • Author(s)
      Thunnissen E., Beasley M. B., Borczuk A., Dacic S., Kerr K. M., Lissenberg-Witte B., ...Invasion Working Group
    • Journal Title

      J Thorac Oncol

      Volume: 18 Pages: 447-462

    • DOI

      10.1016/j.jtho.2022.11.026

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project2023

    • Author(s)
      Tao K., Yamazaki F., Kubo T., Sunami K., Kumamoto T., Arakawa A., ...Ogawa C.
    • Journal Title

      JCO Precis Oncol

      Volume: 7 Pages: e2200266

    • DOI

      10.1200/PO.22.00266

    • Peer Reviewed
  • [Journal Article] Whole Exome Sequencing of Thymoma Patients Exhibiting Exceptional Responses to Pemetrexed Monotherapy2023

    • Author(s)
      Tanaka T., Goto Y., Horie M., Masuda K., Shinno Y., Matsumoto Y., ...Ohe Y.
    • Journal Title

      Cancers (Basel)

      Volume: 15 Pages: 0

    • DOI

      10.3390/cancers15164018

  • [Journal Article] Real-world study of next-generation sequencing diagnostic biomarker testing for patients with lung cancer in Japan2023

    • Author(s)
      Takahashi T., Nishio M., Nishino K., Yoshiki Y., Shiraiwa N., Emir B., ...Nishio K.
    • Journal Title

      Cancer Sci

      Volume: 114 Pages: 2524-2533

    • DOI

      10.1111/cas.15752

    • Peer Reviewed / Open Access
  • [Journal Article] Impact of age for overall survival in head and neck sarcoma2023

    • Author(s)
      Suzuki H., Takano G., Tsukushi S., Ando M., Yatabe Y., Kodaira T., ...Hanai N.
    • Journal Title

      Medicine (Baltimore)

      Volume: 102 Pages: e32966

    • DOI

      10.1097/MD.0000000000032966

    • Peer Reviewed
  • [Journal Article] Keratin-positive fibrotic extraskeletal myxoid chondrosarcoma: a close mimic of myoepithelial tumour2023

    • Author(s)
      Sugino H., Iwata S., Satomi K., Mori T., Nobusawa S., Nagashima T., ...Yoshida A.
    • Journal Title

      Histopathology

      Volume: 82 Pages: 937-945

    • DOI

      10.1111/his.14882

    • Peer Reviewed
  • [Journal Article] Radiological precursor lesions of lung squamous cell carcinoma: Early progression patterns and divergent volume doubling time between hilar and peripheral zones2023

    • Author(s)
      Sugawara H., Yatabe Y., Watanabe H., Akai H., Abe O., Watanabe S. I. and Kusumoto M.
    • Journal Title

      Lung Cancer

      Volume: 176 Pages: 31-37

    • DOI

      10.1016/j.lungcan.2022.12.007

    • Peer Reviewed
  • [Journal Article] Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population2023

    • Author(s)
      Shi J., Shiraishi K., Choi J., Matsuo K., Chen T. Y., Dai J., ...Lan Q.
    • Journal Title

      Nat Commun

      Volume: 14 Pages: 3043

    • DOI

      10.1038/s41467-023-38196-z

    • Peer Reviewed
  • [Journal Article] Molecular pathology quality control in Southeast Asia: Results of a multiregional quality assurance study from MASTER KEY Asia2023

    • Author(s)
      Okuma H. S., Yoshida H., Kobayashi Y., Arakaki M., Mizoguchi C., Inagaki L., ...Yatabe Y.
    • Journal Title

      Cancer Sci

      Volume: 114 Pages: 2664-2673

    • DOI

      10.1111/cas.15790

    • Peer Reviewed
  • [Journal Article] Reply to the Letter to the Editor From He Y et al2023

    • Author(s)
      Okubo Y. and Yatabe Y.
    • Journal Title

      J Thorac Oncol

      Volume: 18 Pages: e46-e48

    • DOI

      10.1016/j.jtho.2023.02.006

    • Peer Reviewed
  • [Journal Article] Strategic Approach to Heterogeneity Analysis of Cutaneous Adnexal Carcinomas Using Computational Pathology and Genomics2023

    • Author(s)
      Nishimura Y., Ryo E., Inoue S., Kawazu M., Ueno T., Namikawa K., ...Mori T.
    • Journal Title

      JID Innov

      Volume: 3 Pages: 100229

    • DOI

      10.1016/j.xjidi.2023.100229

    • Peer Reviewed
  • [Journal Article] Concordance between cryobiopsy and forceps biopsy specimens in assessment of immunohistochemistry staining for non-small cell lung carcinoma2023

    • Author(s)
      Nishimatsu K., Matsumoto Y., Kashima J., Imabayashi T., Uchimura K., Furuse H., ...Yatabe Y.
    • Journal Title

      Transl Lung Cancer Res

      Volume: 12 Pages: 1245-1255

    • DOI

      10.21037/tlcr-22-621

    • Peer Reviewed
  • [Journal Article] KLF4 c.A1322C Mutation Is a Consistent and Specific Genetic Feature of Raspberry-like Foveolar-type Adenoma of the Stomach2023

    • Author(s)
      Naka T., Hashimoto T., Yoshida T., Yatabe Y. and Sekine S.
    • Journal Title

      Am J Surg Pathol

      Volume: 47 Pages: 521-523

    • DOI

      10.1097/PAS.0000000000002012

    • Peer Reviewed
  • [Journal Article] Sporadic and Familial Adenomatous Polyposis-associated Foveolar-type Adenoma of the Stomach2023

    • Author(s)
      Naka T., Hashimoto T., Cho H., Tanabe N., Yoshida T., Yatabe Y., ...Sekine S.
    • Journal Title

      Am J Surg Pathol

      Volume: 47 Pages: 91-101

    • DOI

      10.1097/PAS.0000000000001949

    • Peer Reviewed
  • [Journal Article] Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors2023

    • Author(s)
      Naito Y., Mishima S., Akagi K., Hayashi N., Hirasawa A., Hishiki T., ...Baba E.
    • Journal Title

      Int J Clin Oncol

      Volume: 28 Pages: 827-840

    • DOI

      10.1007/s10147-023-02345-7

    • Peer Reviewed
  • [Journal Article] Dynamics of recurrence after curative resection of nonsmall cell lung cancer2023

    • Author(s)
      Muraoka Y., Yotsukura M., Yoshida Y., Nakagawa K., Shiraishi K., Kohno T., ...Watanabe S. I.
    • Journal Title

      J Surg Oncol

      Volume: 128 Pages: 1205-1212

    • DOI

      10.1002/jso.27395

    • Peer Reviewed
  • [Journal Article] Promoter swapping of truncated PDGFRB drives Ph-like acute lymphoblastic leukemia2023

    • Author(s)
      Miyazaki B., Ueno T., Sugiyama M., Kojima S., Arakawa A., Tao K., ...Tanaka Y.
    • Journal Title

      NPJ Precis Oncol

      Volume: 7 Pages: 132

    • DOI

      10.1038/s41698-023-00485-7

    • Peer Reviewed
  • [Journal Article] Expert Consensus Recommendations on Biomarker Testing in Metastatic and Nonmetastatic NSCLC in Asia2023

    • Author(s)
      Mitsudomi T., Tan D., Yang J. C., Ahn M. J., Batra U., Cho B. C., ...Yatabe Y.
    • Journal Title

      J Thorac Oncol

      Volume: 18 Pages: 436-446

    • DOI

      10.1016/j.jtho.2022.10.021

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with high tumor mutational burden tumors2023

    • Author(s)
      Mishima S., Naito Y., Akagi K., Hayashi N., Hirasawa A., Hishiki T., ...Baba E.
    • Journal Title

      Int J Clin Oncol

      Volume: 28 Pages: 941-955

    • DOI

      10.1007/s10147-023-02360-8

    • Peer Reviewed
  • [Journal Article] Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition2023

    • Author(s)
      Mishima S., Naito Y., Akagi K., Hayashi N., Hirasawa A., Hishiki T., ...Baba E.
    • Journal Title

      Int J Clin Oncol

      Volume: 28 Pages: 1237-1258

    • DOI

      10.1007/s10147-023-02397-9

    • Peer Reviewed
  • [Journal Article] KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing2023

    • Author(s)
      Lim T. K. H., Skoulidis F., Kerr K. M., Ahn M. J., Kapp J. R., Soares F. A. and Yatabe Y.
    • Journal Title

      Lung Cancer

      Volume: 184 Pages: 107293

    • DOI

      10.1016/j.lungcan.2023.107293

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1,, or RET Fusions2023

    • Author(s)
      Kojima N., Mori T., Motoi T., Kobayashi E., Yoshida M., Yatabe Y., ...Yoshida A.
    • Journal Title

      Mod Pathol

      Volume: 36 Pages: 100083

    • DOI

      10.1016/j.modpat.2022.100083

    • Peer Reviewed
  • [Journal Article] Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland2023

    • Author(s)
      Kobayashi K., Kawazu M., Yoshimoto S., Ueno T., Omura G., Saito Y., ...Mori T.
    • Journal Title

      Lab Invest

      Volume: 103 Pages: 100213

    • DOI

      10.1016/j.labinv.2023.100213

    • Peer Reviewed
  • [Journal Article] Fine-needle biopsy with 19G needle is effective in combination with endoscopic ultrasound-guided tissue acquisition for genomic profiling of unresectable pancreatic cancer2023

    • Author(s)
      Ikeda G., Hijioka S., Nagashio Y., Maruki Y., Ohba A., Hisada Y., ...Okusaka T.
    • Journal Title

      Dig Endosc

      Volume: 35 Pages: 124-133

    • DOI

      10.1111/den.14423

    • Peer Reviewed
  • [Journal Article] A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer2023

    • Author(s)
      Hashimoto T., Takayanagi D., Yonemaru J., Naka T., Nagashima K., Machida E., ...Sekine S.
    • Journal Title

      Br J Cancer

      Volume: 129 Pages: 1176-1183

    • DOI

      10.1038/s41416-023-02382-z

    • Peer Reviewed
  • [Journal Article] Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma2023

    • Author(s)
      Haga Y., Sakamoto Y., Kajiya K., Kawai H., Oka M., Motoi N., ...Suzuki A.
    • Journal Title

      Nat Commun

      Volume: 14 Pages: 8375

    • DOI

      10.1038/s41467-023-43732-y

    • Peer Reviewed
  • [Journal Article] A case of vasculogenic mesenchymal tumor in the mediastinum: whole-exome sequencing reveals origin from pre-existing germ cell tumor2023

    • Author(s)
      Fujii H., Yamada Y., Yamamura K., Ishida Y., Tsujimura M., Matsumoto K., ...Haga H.
    • Journal Title

      Virchows Arch

      Volume: 482 Pages: 923-927

    • DOI

      10.1007/s00428-023-03529-2

    • Peer Reviewed
  • [Journal Article] Clinical and pathological features of second primary neoplasms arising in head and neck reconstructive skin flaps2023

    • Author(s)
      Eguchi K., Kobayashi K., Honma Y., Ryo E., Sakyo A., Yokoyama K., ...Mori T.
    • Journal Title

      Sci Rep

      Volume: 13 Pages: 11214

    • DOI

      10.1038/s41598-023-38122-9

    • Peer Reviewed
  • [Presentation] Optimizing the approaches to detect MET alterations in advanced NSCLC: The role of NGS-based molecular testing. Focus on Targeting MET Alterations in Advanced NSCLC: A Webinar for Asian Physicians2023

    • Author(s)
      Yasushi Yatabe
    • Organizer
      ACE Oncology Web Semina
  • [Presentation] Adjuvant Trials in NSCLC ? What Does This Mean for Pathology/Biomarkers.2023

    • Author(s)
      Yasushi Yatabe
    • Organizer
      World Conference of Lung Cancer 2023
  • [Presentation] The Future of Biomarkers in Immunotherapy2023

    • Author(s)
      Yasushi Yatabe
    • Organizer
      World Conference of Lung Cancer 2023
  • [Presentation] がんの病理組織を用いた空間解析最前線2023

    • Author(s)
      谷田部恭
    • Organizer
      第82回日本癌学会学術総会
  • [Presentation] 厚労省・PMDA 、日本癌治療学会、日本臨床腫瘍学会共催ワークショップ 「CDx 制度の成熟と現在の問題」.2023

    • Author(s)
      谷田部恭
    • Organizer
      第64回日本肺癌学会学術集会
  • [Presentation] Molecular Landscape of Mucinous Carcinoma. Novel Omics in Lung Cancer2023

    • Author(s)
      Yasushi Yatabe
    • Organizer
      Korean Lung Cancer Conference

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Published: 2024-12-25  

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