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Germline or somatic mutations in genes encoding microRNAs as biomarkers predicting the risk of adult T-cell leukemia/lymphoma

Journal of Human Genetics (2025)Cite this article

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Abstract

Single nucleotide polymorphisms in microRNA genes (miRNA-SNPs) can alter miRNA maturation or target mRNA recognition, resulting in gain- or loss-of-function, and are associated with various diseases. This study aimed to identify miRNA-SNPs or somatic mutations in miRNA gens that could serve as biomarkers for the onset or progression of adult T-cell lymphoma-leukemia (ATLL), using next-generation sequencing (NGS) targeting 1809 pre-miRNA genes. Genomic DNA extracted from peripheral blood samples from 31 ATLL patients with low human T-cell leukemia virus type-1 (HTLV-1) proviral loads and 28 healthy subjects was analyzed. Fourteen miRNA-SNPs with significantly different allele frequencies were between the two groups were identified. To determine whether the observed variants were germline or somatic, miRNA-SNPs detected in blood-derived DNA were compared with those from saliva-derived DNA in 6 out of 31 patients. Concordant results between the two sources suggested the variants were germline SNPs. Furthermore, comparison of blood-derived DNA samples from 10 ATLL patients collected during low and high HTLV-1 proviral load periods revealed 10 somatic mutations in pre-miRNA genes, including pre-mir-142, present only in high proviral load samples. These somatic mutations may serve as markers of ATLL progression. In conclusion, out comprehensive NGS analysis identified both germline miRNA-SNPs and somatic mutations that may act as biomarkers for the onset or progression of ATLL. Future studies with larger cohorts will be essential to validate their clinical utility.

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Acknowledgements

The authors thank Dr. Koji Kato (Department of Medicine and Biosystemic Science, Kyusyu University Graduate School of Medical Sciences, Fukuoka, Japan), Prof. Shigeki Ito (Hematology & Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Shiwa-gun, Yahaba-cho, Japan), Dr. Shinobu Tamura (Kinan Hospital, Tanabe, Japan), Dr. Yasuhiro Nagamachi (Department of Hematology, Sapporo Kiyota Hospital) and Dr. Ilseung Choi (Hematology and Cell Therapy, NHO Kyushu Cancer center, Fukuoka, Japan) for their contributions to this study.

Funding

This study was supported by a grant from the Ministry of Health, Labor, and Welfare (MHLW) of the Japanese government (Initiative to facilitate development of innovative drug, medical devices, and cellular & tissue-based product) [no grant number].

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Authors and Affiliations

  1. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan

    Shimon Nakashima, Masataka Nakano, Tatsuki Fukami & Miki Nakajima

  2. WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan

    Masataka Nakano, Tatsuki Fukami & Miki Nakajima

  3. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Takashi Ishida, Masaki Ri & Shinsuke Iida

  4. Division of Blood Transfusion and Cell Therapy, Nagoya City University Hospital, Nagoya, Japan

    Masaki Ri

  5. Department of Hematology and Rheumatology, Kagoshima University Hospital, Kagoshima, Japan

    Kenji Ishitsuka

  6. National Hospital Organization Osaka Minami Medical Center, Osaka, Japan

    Go Eguchi & Yasuhiro Maeda

  7. Department of Dermatology, Imamura General Hospital, Kagoshima, Japan

    Kentaro Yonekura

  8. Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University Hospital, Fukuoka, Japan

    Hidenori Sasaki

  9. Department of Tumor Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Ryuzo Ueda

  10. Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan

    Makoto Osabe & Masahiro Tohkin

Authors
  1. Shimon Nakashima
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  2. Masataka Nakano
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  3. Tatsuki Fukami
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  15. Miki Nakajima
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Contributions

Conceptualization, MT, and MiN; methodology, SN, and MiN; validation, SN, MaN, and TF; formal analysis, SN; investigation, SN; resources, TI, MR, KI, GE, YM, KY, HS, and SI; data curation, SN, MiN, and MO; writing-original draft preparion, SN; writing-review and editing, MiN, TI, SI, and MT; visualization, SN, supervision, RU; project administration, MT; funding acquisition, MT. All authors have read and agreed to publish this manuscript.

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Correspondence to Miki Nakajima.

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Nakashima, S., Nakano, M., Fukami, T. et al. Germline or somatic mutations in genes encoding microRNAs as biomarkers predicting the risk of adult T-cell leukemia/lymphoma. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01417-y

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