研究者詳細 - 時野　隆至

論文 - 時野　隆至

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メラノーマ細胞におけるtumor mutation burden及びmicrosatellite instabilityに対するtemozolomideの影響

澤田匡秀, 肥田時征, 神谷崇文, 箕輪智幸, 加藤潤史, 黄倉真恵, 井戸川雅史, 時野隆至, 宇原久

日本皮膚悪性腫瘍学会学術大会プログラム・抄録集 ( (一社)日本皮膚悪性腫瘍学会 ) 39回 229 - 229 2023年06月

Prospective observational study of monitoring gene alterations in plasma cell-free DNA using droplet digital PCR system during anti-EGFR antibody treatment in patients with RAS wild-type advanced colorectal cancer.

Naoki Takahashi, Keishi Nakamura, Yosuke Kito, Eiji Kubota, Masako Asayama, Yosuke Kumekawa, Hiroki Hara, Tomohiro Matsushima, Kunihiro Tsuji, Hiromi Kataoka, Akihiro Tsuyada, Yasushi Sasaki, Masashi Idogawa, Takashi Tokino, Takeshi Sawada

Journal of Clinical Oncology ( American Society of Clinical Oncology (ASCO) ) 41 ( 4_suppl ) 172 - 172 2023年02月

172 Background: Anti-EGFR antibody is recommended as one of the standard treatments in patients with RAS wild-type advanced colorectal cancer (CRC). Few reports have evaluated low-frequency subclones of alterations in EGFR signaling pathway genes in plasma cell-free DNA (cfDNA) during anti-EGFR treatment in prospective cohort of advanced CRC patients. Methods: Key inclusion criteria of this study was as follows: 20 years old and over, performance status 0 to 2, metastatic or recurrent CRC (adenocarcinoma), RAS wild-type CRC diagnosed by PCR-rSSO using tumor tissue, no prior use of anti-EGFR antibody. Plasma samples were prospectively collected at pre-treatment, at 4, 10 weeks, every 10 weeks thereafter, and at the end of the anti-EGFR treatment. With QX200 Droplet Digital PCR platform, we analyzed hotspot mutations of KRAS, NRAS, BRAF, and PIK3CA and copy number (CN) variant of HER2 and MET using plasma samples of pre- and post-treatment as well as during treatment (limited to patients with any gene alterations at pre- and post-treatment). Results: Total 50 patients were registered in this study, but 3 patients were excluded because inclusion criteria were not met. Finally, 47 patients were included in full analysis set. In 15 patients (31.9%), genetic alterations including KRAS (G12G13: 10.1%, A59Q61: 2.2%), NRAS (G12G13: 2.2%, Q61: 2.1%), BRAF (V600: 6.4%) , PIK3CA (E545: 4.3%, H1047: 4.3%) , and HER2 (amplification: 6.5%) were detected in pre-treatment samples. Analysis of pre-treatment samples showed that response rates of patients with any gene alterations (N = 13) and that without any gene alterations (N = 29) were 30.8% and 58.6%, respectively (p = 0.095). When the cut-off of variant allele frequency (VAF) was set as 0.5% in patients with any gene mutations, the response rates for cases with VAF ≥0.5% (N = 6) and those with VAF < 0.5% (N = 7) were 0% and 57.1%, respectively (p = 0.049). Among 41 patients with detectable target lesions by CT scan, there was significant difference in percentage of best tumor shrinkage between patients with gene alterations and those without gene alterations (32.1% vs 10.5%, p = 0.037), when cut-off VAF of any gene mutations was set as 0.5% and cut-off CN of HER2 or MET was set as 4 at pre-treatment. Due to dynamics of each gene alteration in cfDNA during treatment, mutations of KRAS A59Q61, NRAS Q61, and MET amplification were characterized as acquired alterations which were newly detected after the administration of anti-EGFR antibodies. Conclusions: Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923 .

DOI

抗PD-1抗体が著効したNF1変異型末端型メラノーマの1例

松田宇充, 加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 黄倉真恵, 宇原久, 井戸川雅史, 時野隆至

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 133 ( 2 ) 271 - 272 2023年02月

MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway.

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

BMC cancer 23 ( 1 ) 85 - 85 2023年01月 [国際誌]

BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

DOI PubMed

抗PD-1抗体が著効したNF1-mutant acral melanoma肝転移の1例

松田宇充, 加藤潤史, 肥田時征, 堀本浩平, 佐藤さゆり, 黄倉真恵, 宇原久, 井戸川雅史, 時野隆至

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 132 ( 12 ) 2699 - 2699 2022年11月

CRISPRを用いた遺伝子活性化システムによる腫瘍細胞株におけるlncRNAの網羅的機能スクリーニング(Comprehensive screening of long noncoding RNAs(lncRNAs) based on CRISPR-mediated gene activation in cancer cells)

平野朋美, 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 ) 81回 P - 3096 2022年09月

がん遺伝子パネル検査解析支援ソフトウェア「Varporter」の開発(The development of Varporter, a software supporting the evaluation of cancer gene panel test.)

井戸川雅史, 平野朋美, 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 ) 81回 J - 2034 2022年09月

頭頸部扁平上皮癌におけるctDNAモニタリングの特徴(The characteristics of ctDNA monitoring in head and neck squamous cell carcinoma)

古後龍之介, 真子知美, 岩谷岳, 開勇人, 西塚哲, 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 ) 81回 P - 1283 2022年09月

膵臓がんにおける新規予後予測遺伝子と1炭素代謝経路の関係(A relationship between the novel prognosticator gene in malignant pancreatic cancer and one-carbon metabolism)

丹下正一朗, 平野朋美, 井戸川雅史, 平田英周, 井本逸勢, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 81回 P - 2314 2022年09月

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

Hiroki Murai, Takahiro Kodama, Kazuki Maesaka, Shoichiro Tange, Daisuke Motooka, Yutaka Suzuki, Yasuyuki Shigematsu, Kentaro Inamura, Yoshihiro Mise, Akio Saiura, Yoshihiro Ono, Yu Takahashi, Yota Kawasaki, Satoshi Iino, Shogo Kobayashi, Masashi Idogawa, Takashi Tokino, Tomomi Hashidate-Yoshida, Hideo Shindou, Masanori Miyazaki, Yasuharu Imai, Satoshi Tanaka, Eiji Mita, Kazuyoshi Ohkawa, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Hidetoshi Eguchi, Eiichi Morii, Tetsuo Takehara

Hepatology (Baltimore, Md.) 77 ( 1 ) 77 - 91 2022年05月 [国際誌]

BACKGROUND&AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES&RESULTS: We performed RNA-seq of tumor tissues in 113 nonviral HCC patients and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into 3 molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with CTNNB1 mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T-cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Steatotic HCC patients, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

DOI PubMed

Mutation Analysis of Radioresistant Early-Stage Cervical Cancer.

Tae Oike, Yoshihito Sekiguchi, Yuya Yoshimoto, Takahiro Oike, Ken Ando, Wenchao Gu, Yasushi Sasaki, Takashi Tokino, Akira Iwase, Tatsuya Ohno

International journal of molecular sciences 23 ( 1 ) 2021年12月 [国際誌]

Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.

DOI PubMed

DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes.

Yui Hatanaka, Takeshi Niinuma, Hiroshi Kitajima, Koyo Nishiyama, Reo Maruyama, Kazuya Ishiguro, Mutsumi Toyota, Eiichiro Yamamoto, Masahiro Kai, Akira Yorozu, Shohei Sekiguchi, Kazuhiro Ogi, Hironari Dehari, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino, Akihiro Miyazaki, Hiromu Suzuki

Scientific reports 11 ( 1 ) 20438 - 20438 2021年10月 [国際誌]

Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

DOI PubMed

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

Ryosuke Fujisawa, Takeshi Iwaya, Fumitaka Endo, Masashi Idogawa, Noriyuki Sasaki, Hayato Hiraki, Shoichiro Tange, Tomomi Hirano, Yuka Koizumi, Masakazu Abe, Tomoko Takahashi, Mizunori Yaegashi, Yuji Akiyama, Mari Masuda, Akira Sasaki, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S Nishizuka

Carcinogenesis 42 ( 10 ) 1239 - 1249 2021年09月 [国際誌]

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

DOI PubMed

Dead or alive? Pitfall of survival analysis with TCGA datasets.

Masashi Idogawa, Masayo Koizumi, Tomomi Hirano, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

Cancer biology & therapy 22 ( 10-12 ) 1 - 2 2021年09月 [国際誌]

We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

DOI PubMed

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus.

Tomoyuki Minowa, Takafumi Kamiya, Tokimasa Hida, Masae Okura, Junji Kato, Masashi Idogawa, Shoichiro Tange, Tomomi Hirano, Takashi Tokino, Hisashi Uhara

The Journal of dermatology 48 ( 8 ) 1268 - 1272 2021年08月 [国際誌]

A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

DOI PubMed

Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo.

Naoki Tanimizu, Norihisa Ichinohe, Yasushi Sasaki, Tohru Itoh, Ryo Sudo, Tomoko Yamaguchi, Takeshi Katsuda, Takafumi Ninomiya, Takashi Tokino, Takahiro Ochiya, Atsushi Miyajima, Toshihiro Mitaka

Nature communications 12 ( 1 ) 3390 - 3390 2021年06月 [国際誌]

In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. Although liver organoids have been reported, it is not clear whether the functional connection between hepatocytes and cholangiocytes is recapitulated in those organoids. Here, we report the generation of a hepatobiliary tubular organoid (HBTO) using mouse hepatocyte progenitors and cholangiocytes. Hepatocytes form the bile canalicular network and secrete metabolites into the canaliculi, which are then transported into the biliary tubular structure. Hepatocytes in HBTO acquire and maintain metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we establish functional liver tissue incorporating a bile drainage system ex vivo. HBTO enable us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.

DOI PubMed

カスタムパネルシーケンスを用いた日本人メラノーマのドライバー遺伝子の検出

肥田時征, 井戸川雅史, 堀本浩平, 加藤潤史, 佐藤さゆり, 藤岡茉生, 丹下正一朗, 時野隆至, 宇原久

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 ) 131 ( 5 ) 1363 - 1363 2021年05月

ALK-positive atypical Spitz tumour with conspicuous rosette-like structures.

Tomoyuki Minowa, Tokimasa Hida, Kohei Horimoto, Junji Kato, Takafumi Kamiya, Shintaro Sugita, Masashi Idogawa, Toshiaki Saida, Tadashi Hasegawa, Takashi Tokino, Hisashi Uhara

European journal of dermatology : EJD 31 ( 2 ) 256 - 258 2021年04月 [国際誌]

DOI PubMed

Circulating tumor DNAの初期変動を用いた食道癌化学療法効果予測に関する検討

藤澤良介, 岩谷岳, 遠藤史隆, 佐々木教之, 二階春香, 馬場誠朗, 秋山有史, 開勇人, 小泉優香, 阿部正和, 片桐弘勝, 木村聡元, 大塚幸喜, 井戸川雅史, 新田浩幸, 佐々木章, 佐々木泰史, 時野隆至, 西塚哲

日本外科学会定期学術集会抄録集 ( (一社)日本外科学会 ) 121回 SF - 1 2021年04月

Circulating tumor DNAの初期変動を用いた食道癌化学療法効果予測に関する検討

日本外科学会定期学術集会抄録集 ( (一社)日本外科学会 ) 121回 SF - 1 2021年04月

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