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• Genome-wide DNA methylation profiling of pleomorphic carcinoma of the lung

  Nakagomi T., Fujimoto M., Kuriyama S., Hishida T., Asamura H., Asakura K., Kanai Y., Arai E.

  Human Pathology 167 2026.01

  ISSN  00468177

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  The aim of this study was to clarify the significance of DNA methylation alterations in the histological and clinicopathological diversity of pleomorphic carcinoma of the lung. Eleven samples of non-cancerous lung tissue (N), and 10 and 11 samples of non-sarcomatoid and sarcomatoid components of cancerous tissue (T), respectively, were microdissected from formalin-fixed paraffin-embedded specimens of 11 patients with pleomorphic carcinoma of the lung. Genome-wide DNA methylation analysis was performed on all 32 microdissected tissue samples using the Infinium MethylationEPIC BeadChip. Principal component analysis revealed that DNA methylation alterations are associated with lung carcinogenesis and that the diversity of DNA methylation profiles may increase during transition of the non-sarcomatoid component to the sarcomatoid component. Genes showing differences in DNA methylation level between 11 N samples and all 21 T samples regardless of whether they were non-sarcomatoid or sarcomatoid, and whose transcription levels are potentially regulated by DNA methylation, were accumulated in the cadherin, Wnt and angiogenesis pathways. Significant differences in DNA methylation level between non-sarcomatoid and sarcomatoid components potentially resulting in transcription alterations were observed in the OCIAD2, LAMB1 and DKK3 genes. Sarcomatoid component-specific DNA hypomethylation relative to N samples of C2orf27A and COX6C was correlated with clinicopathological parameters such as lymph vessel invasion and higher pathological stage, respectively. Sarcomatoid component-specific DNA hypomethylation of TSKU, PLAU, PLEKHG4, RPSAP52, XBP1 and TRIM2 was correlated with both recurrence-free and overall survival. These data suggest that the DNA methylation alterations associated with sarcomatoid change may participate in malignant progression and determine patient outcome.

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• Prognostically Significant Glycan Profiles of Clear Cell Renal Cell Carcinoma Identified by Integrated Glycome–Methylome Analysis

  Kitazume Y., Arai E., Fujimoto M., Ohara K., Matsuda A., Kakuda S., Fujimoto H., Maeshima A.M., Hiraoka N., Yoshida T., Kuno A., Kanai Y.

  Pathology International 76 ( 1 )  2026.01

  ISSN  13205463

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  The aim of this study was to clarify the clinicopathological significance of the glycan profile of clear cell renal cell carcinoma (ccRCC). Comprehensive glycomic analysis and methylome analysis were performed using 50 paired nontumorous renal tissue (N) and tumorous tissue (T) specimens from patients with ccRCC. In comparison to N samples, T samples showed higher signal intensities for lectins recognizing high-mannose glycans and lower intensity for fucose and sialic acid, indicating that N-type glycans remain “immature” in ccRCCs. Hierarchical clustering using the signal intensities of lectins recognizing high-mannose glycans, fucose, and sialic acid divided T samples into Cluster A (n = 32) and Cluster B (n = 18). In Cluster B, the incidence of tumor-related death was higher (p = 0.017) and overall survival was lower (p = 0.019). Moreover, asialo-type glycans and N-acetyllactosamine residues, which are recognized by lectins DSA, ECA, and PHA-E, had an impact on both recurrence-free and overall survival. The expression of glycogenes, such as MGAT1, ST6GAL1, and TUSC3, may be epigenetically regulated. These results suggest that the glycan profile may be at least partly attributable to epigenetic regulation of glycogenes, and that comprehensive glycan profiling could provide clinically useful information for patients with ccRCC.

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• Plasma cell-free DNA methylation profile before afatinib treatment is associated with progression-free and overall survival of patients with epidermal growth factor receptor gene mutation-positive non-small cell lung cancer

  Fujimoto M., Yasuda H., Arai E., Nakajima M., Takata S., Morikawa K., Tanaka H., Itani H., Honda T., Horiuchi K., Watanabe K., Nakagawa H., Nakahara Y., Seki Y., Bessho A., Takahashi N., Hayashi K., Endo T., Takeyama K., Maekura T., Takigawa N., Kawase A., Endoh M., Nemoto K., Kishi K., Soejima K., Okuma Y., Togashi A., Matsutani N., Seki N., Kanai Y.

  Clinical Epigenetics 17 ( 1 )  2025.12

  ISSN  18687075

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  Background: The present study aimed to clarify the clinical significance of the cell-free DNA (cfDNA) methylation profile of patients with non-small cell lung cancer (NSCLC) showing the epidermal growth factor receptor (EGFR) gene mutation. Methods: In 103 patients, genome-wide DNA methylation analysis using Infinium Methylation EPIC array was performed using samples of pre-tyrosine kinase inhibitor afatinib-treatment plasma cfDNA (n = 101) and post-afatinib cfDNA (n = 84). Results: Principal component analysis indicated that the cfDNA methylation profile was altered after afatinib treatment. Hierarchical clustering using the pre-afatinib cfDNA methylation profile revealed that cases with a fatal outcome were accumulated in specific clusters. Moreover, Kaplan–Meier analysis showed that the pre-afatinib cfDNA methylation profile was significantly associated with both progression-free survival (PFS) and overall survival (OS), whereas the post-afatinib profile was not. The genes for which pre-afatinib cfDNA methylation levels were associated with PFS were accumulated in the cadherin, Wnt, and EGFR signaling pathways. Activation of EGFR-related signaling due to DNA methylation alterations might overturn the effect of afatinib. Pre-afatinib levels of CEP170 and CHCHD6 cfDNA methylation were associated with both PFS and OS. Both pre- and post-afatinib cfDNA methylation levels of SLC9A3R2 and INTS1 were associated with bone metastasis. Using the cfDNA methylation levels at two CpG sites, cg12721600 and cg05905155, patients showing an overall response were predicted with a sensitivity of 96% or more. Conclusions: The non-invasively measurable cfDNA methylation profile may reflect the corresponding profile in cancer cells, and that pre-treatment measurement may provide clinically useful information on EGFR mutation-positive NSCLC.

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• Genome-wide DNA methylation profiling of blood samples from patients with major depressive disorder: correlation with symptom heterogeneity

  Nagao Y., Fujimoto M., Tian Y., Kameyama S., Hattori K., Hidese S., Kunugi H., Kanai Y., Arai E.

  Journal of Psychiatry and Neuroscience 50 ( 2 ) E112 - E124 2025.04

  ISSN  11804882

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  Background: Alterations in DNA, such as DNA methylation, may be key molecular events involved in the development of major depressive disorder (MDD). We sought to clarify correlations between DNA methylation profiles and symptom heterogeneity among patients with MDD. Methods: We conducted a genome-wide DNA methylation analysis of blood samples from patients with MDD and controls, using the Infinium MethylationEPIC BeadChip. Results: We analyzed 283 blood samples, including 141 from an initial cohort (69 patients with MDD, 72 controls) and 142 from a second validation cohort (67 patients with MDD, 75 controls). After adjustment for age, sex, and blood cell heterogeneity, DNA methylation status at 2699 CpG sites tended to differ between patients with MDD and controls in both the initial and second cohorts. Hierarchical clustering of patients based on DNA methylation status at these 2699 CpG sites revealed a significant correlation with scores for GRID-Hamilton Depression Rating Scale (GRID-HAMD) items (depressed mood, guilt, early insomnia, middle insomnia, work and activities, psychic anxiety, loss of appetite, general somatic symptoms, and total score), suggesting the feasibility of severity diagnostics based on blood DNA methylation testing. Pathway over-representation analysis revealed that genes whose DNA methylation status was correlated with epigenetic clustering were accumulated in molecular pathways involved in various cellular functions, especially nerve development. For PLEKHD1, STK10, and FOXK1, DNA methylation levels were inversely correlated with expression levels in the Clinical Proteomic Tumor Analysis Consortium database. DNA hypomethylation of PLEKHD1, STK10, and FOXK1 was correlated with higher GRID-HAMD scores in both cohorts. Limitations: Although we performed marker exploration using 2 cohorts including 283 participants, the heterogeneity of the molecular mechanisms operating in MDD might necessitate a larger cohort for establishment of criteria with sufficient diagnostic impact. Conclusion: These findings indicate that the DNA methylation status of specific genes may correlate with the severity of MDD symptoms, and that genome-wide DNA methylation analysis of blood samples would be useful for clarifying the DNA methylation profiles related to symptom heterogeneity.

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• Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes

  Marumo T., Yoshida N., Inoue N., Yamanouchi M., Ubara Y., Urakami S., Fujii T., Takazawa Y., Ohashi K., Kawarazaki W., Nishimoto M., Ayuzawa N., Hirohama D., Nagae G., Fujimoto M., Arai E., Kanai Y., Hoshino J., Fujita T.

  American Journal of Physiology Renal Physiology 327 ( 3 ) F397 - F411 2024.09

  ISSN  1931857X

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  Epigenetic mechanisms are considered to contribute to diabetic nephropathy by maintaining memory of poor glycemic control during the early stages of diabetes. However, DNA methylation changes in the human kidney are poorly characterized, because of the lack of cell type-specific analysis. We examined DNA methylation in proximal tubules (PTs) purified from patients with diabetic nephropathy and identified differentially methylated CpG sites, given the critical role of proximal tubules in the kidney injury. Hypermethylation was observed at CpG sites annotated to genes responsible for proximal tubule functions, including gluconeogenesis, nicotinamide adenine dinucleotide synthesis, transporters of glucose, water, phosphate, and drugs, in diabetic kidneys, whereas genes involved in oxidative stress and the cytoskeleton exhibited demethylation. Methylation levels of CpG sites annotated to ACTN1, BCAR1, MYH9, UBE4B, AFMID, TRAF2, TXNIP, FOXO3, and HNF4A were correlated with the estimated glomerular filtration rate, whereas methylation of the CpG site in RUNX1 was associated with interstitial fibrosis and tubular atrophy. Hypermethylation of G6PC and HNF4A was accompanied by decreased expression in diabetic kidneys. Proximal tubule-specific hypomethylation of metabolic genes related to HNF4A observed in control kidneys was compromised in diabetic kidneys, suggesting a role for aberrant DNA methylation in the dedifferentiation process. Multiple genes with aberrant DNA methylation in diabetes overlapped genes with altered expressions in maladaptive proximal tubule cells, including transcription factors PPARA and RREB1. In conclusion, DNA methylation derangement in the proximal tubules of patients with diabetes may drive phenotypic changes, characterized by inflammatory and fibrotic features, along with impaired function in metabolism and transport. NEW & NOTEWORTHY Cell type-specific DNA methylation patterns in the human kidney are not known. We examined DNA methylation in proximal tubules of patients with diabetic nephropathy and revealed that oxidative stress, cytoskeleton, and metabolism genes were aberrantly methylated. The results indicate that aberrant DNA methylation in proximal tubules underlies kidney dysfunction in diabetic nephropathy. Aberrant methylation could be a target for reversing memory of poor glycemic control.

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• Establishment of diagnostic criteria for upper urinary tract urothelial carcinoma based on genome-wide DNA methylation analysis (本文)

  Fujimoto, Mao

  (慶應義塾大学大学院医学研究科)  2023

• ゲノム網羅的DNAメチル化解析に基づく上部尿路がん診断指標開発

  Fujimoto, Mao

  (慶應義塾大学大学院医学研究科)  2023

• ゲノム網羅的DNAメチル化解析に基づく上部尿路がん診断指標開発

  Fujimoto, Mao

  (慶應義塾大学大学院医学研究科)  2023

Research Projects of Competitive Funds, etc. 【 Display / hide 】

Research Projects of Competitive Funds, etc. 【 Display / hide 】

• 尿中DNAメチル化プロファイリングに基づく非侵襲的上部尿路がん診断法の開発

  2025.04

  -

  2028.03

  若手研究, Principal investigator