Mizuno, Takaaki

写真a

Affiliation

School of Medicine, Center for Cancer Genomics (Shinanomachi)

Position

Project Assistant Professor (Non-tenured)/Project Research Associate (Non-tenured)/Project Instructor (Non-tenured)

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Papers 【 Display / hide 】

  • Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

    Kaneko S., Takasawa K., Asada K., Shiraishi K., Ikawa N., Machino H., Shinkai N., Matsuda M., Masuda M., Adachi S., Takahashi S., Kobayashi K., Kouno N., Bolatkan A., Komatsu M., Yamada M., Miyake M., Watanabe H., Tateishi A., Mizuno T., Okubo Y., Mukai M., Yoshida T., Yoshida Y., Horinouchi H., Watanabe S.I., Ohe Y., Yatabe Y., Saloura V., Kohno T., Hamamoto R.

    Molecular Cancer 23 ( 1 )  2024.12

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    Background: In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. Methods: We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. Results: We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Conclusions: Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

  • Characterizing multi-PIK3CA mutations across cancer types: Toward precision oncology

    Nakamura K., Ishikawa M., Kawano R., Aimono E., Mizuno T., Nohara S., Tanishima S., Hayashi H., Nishihara H., Yamada H., Fujikura T.

    Cancer Medicine 13 ( 14 )  2024.07

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    Background: PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored. Methods: In this study, we analyzed multi-PIK3CA mutations across a diverse pan-cancer cohort comprising 3564 tumors. Results: Multi-PIK3CA mutations were present in 10.3% of all PIK3CA-mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans-orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation. Conclusions: The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans-orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.

  • Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability

    Takasawa K., Asada K., Kaneko S., Shiraishi K., Machino H., Takahashi S., Shinkai N., Kouno N., Kobayashi K., Komatsu M., Mizuno T., Okubo Y., Mukai M., Yoshida T., Yoshida Y., Horinouchi H., Watanabe S.I., Ohe Y., Yatabe Y., Kohno T., Hamamoto R.

    Experimental and Molecular Medicine 56 ( 3 ) 646 - 655 2024.03

    ISSN  12263613

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    DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

  • BRCA1/2 reversion mutations in a pan-cancer cohort

    Nakamura K., Hayashi H., Kawano R., Ishikawa M., Aimono E., Mizuno T., Kuroda H., Kojima Y., Niikura N., Kawanishi A., Takeshita K., Suzuki S., Ueno S., Okuwaki K., Sasaki J., Yamaguchi M., Masuda K., Chiyoda T., Yamagami W., Okada C., Nohara S., Tanishima S., Nishihara H.

    Cancer Science 115 ( 2 ) 635 - 647 2024.02

    ISSN  13479032

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    Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

  • Sketch-based semantic retrieval of medical images

    Kobayashi K., Gu L., Hataya R., Mizuno T., Miyake M., Watanabe H., Takahashi M., Takamizawa Y., Yoshida Y., Nakamura S., Kouno N., Bolatkan A., Kurose Y., Harada T., Hamamoto R.

    Medical Image Analysis 92 2024.02

    ISSN  13618415

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    The volume of medical images stored in hospitals is rapidly increasing; however, the utilization of these accumulated medical images remains limited. Existing content-based medical image retrieval (CBMIR) systems typically require example images, leading to practical limitations, such as the lack of customizable, fine-grained image retrieval, the inability to search without example images, and difficulty in retrieving rare cases. In this paper, we introduce a sketch-based medical image retrieval (SBMIR) system that enables users to find images of interest without the need for example images. The key concept is feature decomposition of medical images, which allows the entire feature of a medical image to be decomposed into and reconstructed from normal and abnormal features. Building on this concept, our SBMIR system provides an easy-to-use two-step graphical user interface: users first select a template image to specify a normal feature and then draw a semantic sketch of the disease on the template image to represent an abnormal feature. The system integrates both types of input to construct a query vector and retrieves reference images. For evaluation, ten healthcare professionals participated in a user test using two datasets. Consequently, our SBMIR system enabled users to overcome previous challenges, including image retrieval based on fine-grained image characteristics, image retrieval without example images, and image retrieval for rare cases. Our SBMIR system provides on-demand, customizable medical image retrieval, thereby expanding the utility of medical image databases.

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

    Shiraishi K., Takahashi A., Momozawa Y., Daigo Y., Kaneko S., Kawaguchi T., Kunitoh H., Matsumoto S., Horinouchi H., Goto A., Honda T., Shimizu K., Torasawa M., Takayanagi D., Saito M., Saito A., Ohe Y., Watanabe S.i., Goto K., Tsuboi M., Tsuchihara K., Takata S., Aoi T., Takano A., Kobayashi M., Miyagi Y., Tanaka K., Suzuki H., Maeda D., Yamaura T., Matsuda M., Shimada Y., Mizuno T., Sakamoto H., Yoshida T., Goto Y., Yoshida T., Yamaji T., Sonobe M., Toyooka S., Yoneda K., Masago K., Tanaka F., Hara M., Fuse N., Nishizuka S.S., Motoi N., Sawada N., Nishida Y., Kumada K., Takeuchi K., Tanno K., Yatabe Y., Sunami K., Hishida T., Miyazaki Y., Ito H., Amemiya M., Totsuka H., Nakayama H., Yokose T., Ishigaki K., Nagashima T., Ohtaki Y., Imai K., Takasawa K., Minamiya Y., Kobayashi K., Okubo K., Wakai K., Shimizu A., Yamamoto M., Iwasaki M., Matsuda K., Inazawa J., Shiraishi Y., Nishikawa H., Murakami Y., Kubo M., Matsuda F., Kamatani Y., Hamamoto R., Matsuo K., Kohno T.

    Cancer Communications 44 ( 2 ) 287 - 293 2024.02

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