Education 【 display / non-display 】

Education 【 display / non-display 】

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  1989

  Osaka University  

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  1989

  Osaka University  

Degree 【 display / non-display 】

Degree 【 display / non-display 】

• Ph. D.

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  Molecular Biology Society of Japan

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  米国癌学会

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  日本癌学会

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  日本分子生物学会

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  Japanese Cancer Association

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Tumor biology  

• Life sciences   Genomics  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   Cancer Research Institute, School of Medicine Cancer Research Institute Dept. of Molecular Biology   Professor  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• 分子生物学

• がんゲノム

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan.

  Tokimasa Hida, Masashi Idogawa, Junji Kato, Yukiko Kiniwa, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Shoichiro Tange, Masae Okura, Ryuhei Okuyama, Takashi Tokino, Hisashi Uhara

  Cancer medicine   13 ( 22 ) e70360  2024.11  [International journal]

  　View Summary

  BACKGROUND: Acral and mucosal melanomas are more prevalent in Asians than in Caucasians, unlike cutaneous melanomas, which are predominant in Caucasians. Recent studies have suggested that non-Caucasian cutaneous melanomas responded less to immune checkpoint inhibitors, highlighting the need for genetic profiling across ethnicities. This study aimed to elucidate the genetic characteristics of Japanese melanomas, which is an under-researched topic. METHODS: Single-nucleotide variants, indels, and copy number alterations in 104 Japanese melanoma patients (37 cutaneous, 52 acral, and 15 mucosal) were analyzed using custom panel sequencing. RESULTS: Driver events were detected in 94% of the cases. Among cutaneous melanoma cases, 76% had BRAF mutations, and 8% had NRAS mutations. In acral melanoma, BRAF (9%), NRAS (17%), KRAS (8%), KIT (19%), and NF1 (7%) mutations were detected. Major driver mutations in mucosal melanoma were detected in NRAS, KRAS, NF1, PTEN, GNAQ, and KIT. The median tumor mutational burden across all melanoma types was 4.6 mutations/Mb, with no significant difference between the cutaneous and acral/mucosal types. Of the 21 patients with both primary and metastatic lesions, 11 showed distinct mutations in each. Potentially actionable mutations were detected in 58 patients in addition to BRAF V600E/K mutations in 31. CONCLUSIONS: This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

  DOI PubMed

• A case of familial progressive hyperpigmentation with or without hypopigmentation presenting with hypopigmented striae along the lines of Blaschko.

  Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Masae Okura, Satoru Sasaki, Takashi Tokino, Hisashi Uhara

  The Journal of dermatology    2024.09  [International journal]

  　View Summary

  Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH.

  DOI PubMed

• Genomic landscape of cutaneous, acral, mucosal, and uveal melanoma in Japan: analysis of clinical comprehensive genomic profiling data.

  Tokimasa Hida, Junji Kato, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

  International journal of clinical oncology    2024.09  [Domestic journal]

  　View Summary

  BACKGROUND: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan. METHODS: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed. RESULTS: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1. CONCLUSION: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

  DOI PubMed

• Mosaic SUFU mutation associated with a mild phenotype of multiple hereditary infundibulocystic basal cell carcinoma syndrome.

  Marina Hamada, Tokimasa Hida, Masashi Idogawa, Shoichiro Tange, Takafumi Kamiya, Masae Okura, Toshiharu Yamashita, Takashi Tokino, Hisashi Uhara

  The Journal of dermatology    2024.08  [International journal]

  　View Summary

  Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants.

  DOI PubMed

• LMNA::NTRK1 Fusion-positive Leiomyosarcoma: Discrepancy between DNA-based Comprehensive Genomic Profiling and RNA Sequencing.

  Norito Suzuki, Masashi Idogawa, Makoto Emori, Kazuyuki Murase, Yohei Arihara, Hajime Nakamura, Makoto Usami, Tomohiro Kubo, Ichiro Kinoshita, Shintaro Sugita, Takashi Tokino, Tadashi Hasegawa, Akihiro Sakurai, Kohichi Takada

  Internal medicine (Tokyo, Japan)   63 ( 15 ) 2215 - 2219  2024.08  [Domestic journal]

  　View Summary

  A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne® CDx (F1). F1 identified an out-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• Molecular mechanisms of suppression of Claudin-1 expression in oral cancer cell lines

  丹下正一朗, 井戸川雅史, 川島秀器, 佐々木泰史, 時野隆至

  日本分子生物学会年会プログラム・要旨集(Web)   46th  2023

  J-GLOBAL

• Identification of novel prognosticator gene in malignant pancreatic cancer

  Shoichiro Tange, Tomomi Hirano, Masashi Idogawa, Eishu Hirata, Issei Imoto, Takashi Tokino

  CANCER SCIENCE ( WILEY )  113  2022.02

  Research paper, summary (international conference)  

• 長鎖非コードRNA lncAC1は大腸癌の進行を促進する

  小泉 昌代, 井戸川 雅史, 丹下 正一朗, 時野 隆至

  日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P14 - 5]  2021.09

• RAS野生型転移性大腸癌患者における循環腫瘍DNA中のRAS、BRAF、PIK3CA変異の同定と腫瘍組織の変異との比較

  澤田 武, 久保田 英嗣, 中村 慶史, 高橋 直樹, 太田 亮介, 井戸川 雅史, 佐々木 泰史, 時野 隆至, 源 利成, 片岡 洋望

  日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P15 - 6]  2021.09

• 症例特異的変異を用いた頭頸部扁平上皮癌におけるctDNAモニタリング

  古後 龍之介, 真子 知美, 岩谷 岳, 西塚 哲, 佐々木 泰史, 井戸川 雅史, 時野 隆至, 中川 尚志

  日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [J14 - 6]  2021.09

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 寿原記念財団研究助成金

  1999  

• 日本癌学会奨励賞

  1998  

• 財団法人ノバルティス科学振興財団研究助成金

  1998  

• 高松宮妃癌研究基金研究助成金

  1996  

• 原口記念癌研究助成基金

  1995  

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 新規がん治療法の開発をめざしたp53との合成致死に関与する遺伝子群の探索

  基盤研究(C)

  Project Year :

  2022.04

  -

  2025.03

   

  時野 隆至

• p53 pathway and its potential targeted therapeutic approach

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2019.04

  -

  2023.03

   

  時野 隆至

  　View Summary

  p53はヒト悪性腫瘍で最も高頻度に変異している遺伝子であるが，「がん抑制遺伝子」であるためp53経路をターゲットとした抗がん剤の開発は遅れている．そのためp53転写ネットワークの全貌を解明することは，がんゲノム情報にもとづいたがん治療に有望な分子標的治療薬の開発につながることが期待できる． 本年度は，p53の活性化に関与する長鎖非コードRNA (long non-coding RNA; lncRNA) を探索した．本研究では，TCGA (The Cancer Genome Atlas)のがんゲノムデータを利用して，正常大腸上皮細胞と比較して大腸がん細胞で高発現し，かつ高発現群で予後不良と相関するlncRNAを10個同定した．このうちの1つのlncRNAに注目し，正常型p53遺伝子をもつ大腸がん細胞株HCT116(p53+/+)においてこのlncRNAをノックダウンし，次にRNAシーケンス (RNA-seq) により発現変動遺伝子を網羅的に解析した． その結果，コントロールHCT116(p53+/+)細胞と比較してこのlncRNAノックダウンHCT116(p53+/+)細胞で，p53の代表的標的遺伝子遺伝子CDKN1A（p21タンパク質をコード）の発現が最も有意に上昇していた．そこで，第16番染色体に位置するこの長鎖非コードRNAをlnc53AC（仮称）と名付けた．p53遺伝子をノックアウトしたHCT116(p53-/-)細胞ではCDKN1A遺伝子の発現上昇は見られず，lnc53ACはp53依存的にCDKN1A遺伝子の転写活性化することを確認した．ボルケーノプロット分析とウエスタンブロット解析により，lnc53ACノックダウンはp53遺伝子を翻訳レベルあるいは翻訳後修飾に影響を及ぼしp53を活性化することがわかった．

• A better understanding of p53 network for cancer therapy

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2016.04

  -

  2020.03

   

  TOKINO Takashi

  　View Summary

  p53 is one of the most important tumor suppressor genes. Thus, understanding p53 network is an important issue. In this study, we identified BRMS1L and ARVCF as novel p53-target genes. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effects. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. We found that BRMS1L is one of the mediators downstream of the p53 pathway, such as p21 activation and survivin suppression. We also revealed the knockdown of ARVCF inhibited p53-induced apoptosis. Our results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Our study indicates that BRMS1L and ARVCF are involved in tumor suppression, and could be therapeutic targets for human cancer.

• 先進ゲノム解析研究推進プラットフォーム

  新学術領域研究（研究領域提案型）『学術研究支援基盤形成』

  Project Year :

  2016

  -

  2021

   

  小原 雄治, 加藤 和人, 川嶋 実苗, 豊田 敦, 鈴木 穣, 三井 純, 林 哲也, 時野 隆至, 黒川 顕, 中村 保一, 野口 英樹, 高木 利久, 岩崎 渉, 森下 真一, 浅井 潔, 笠原 雅弘, 伊藤 武彦, 山田 拓司, 小椋 義俊, 久原 哲, 高橋 弘喜, 瀬々 潤, 榊原 康文

  　View Summary

  ①総括支援活動では、応募の機会増加の要望に応えるため今年度から年2回の公募とした。その結果、合計466の応募課題があり、207課題(44%)を採択した。コロナ禍の影響の中、昨年度より応募数は100件近く増加したが、支援内容の精査や支援経費の限度額設定等により、40%超の採択率を維持した。審査委員はすべてプラットフォーム外の専門家とし、評価が同程度の場合は若手、女性、少額科研費からの課題、初めての応募課題を優先した。支援課題は科研費生物系のほぼすべての分野に渡っており、支援の成果を含む論文として2020年度に161報が発表された。この中には「単核貪食細胞系の分化における遺伝子発現制御機構の包括的解明」(Nature Immunol.)、「キンギョの変異体の表現型多様性を作り上げる分子機構の理解」(Current Biol.)、「植物二次代謝経路のゲノム進化に学ぶ生合成デザイン」(Nature Comm.)など広い分野でのレベルの高い成果が含まれている。拡大班会議や情報解析講習会はオンサイト開催が必要なためにコロナ禍の中で見送ったが、WEB開催としたヒトゲノム研究倫理を考える会は5回開催し、各回約500名が参加した。 ②大規模配列解析拠点ネットワーク支援活動においては、最先端技術を支援に提供するとともに、染色体レベルの高精度ゲノム配列決定、シングルセル・空間遺伝子発現解析等の支援技術高度化を進めた。 ③高度情報解析支援ネットワーク活動では、支援から浮かび上がった課題を解決するソフトウェアの開発を進め、実際の課題への適用を進めた。2020年度には、超高速相同性検索ソフトウェアPZLASTの開発、Hi-Cデータを使ったゲノムアセンブリソフトウエア、ロングリードシミュレータPBSIM2の開発などを進め、②と合わせて24報の論文を発表した。

• New insights into p53 signaling regulation to cure cancer

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2013.04

  -

  2017.03

   

  TOKINO Takashi

  　View Summary

  We found that forkhead transcription factor FOXF1 and intercellular adhesion molecule-2 (ICAM2) are novel target genes of p53. The ectopic expression of FOXF1 and ICAM2 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 and ICAM2 stimulated cell invasion and migration. Our findings suggest that FOXF1 and ICAM2 induction by p53 are on key pathways in inhibiting cancer cell migration and invasion. We also found CRKL oncogene is downregulated by p53 through miR-200s. First, we identified that miR-200s are direct transcriptional targets of p53 and then miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3’-UTR region. The CRKL oncogene encodes an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains and is reported to be overexpressed in a subset of cancer types. Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

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