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Cancer and disease profiles for PTEN pathogenic variants in Japanese population

Journal of Human Genetics volume 70, pages 135–140 (2025)Cite this article

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Abstract

A germline alteration in the PTEN gene causes a spectrum of disorders conceptualized as PTEN hamartoma tumor syndrome (PHTS), which show high risk of tumor development and a highly variable and complex phenotype. The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing. In this study, to understand more PTEN-associated clinical phenotype and PHTS in a Japanese population, we extracted 128 germline PTEN rare variants from 113,535 adult Japanese registered in Biobank Japan (BBJ), and categorized 29 pathogenic/likely pathogenic variants in 30 individuals (0.0264%) with ClinVar classifications and ACMG/AMP guideline for PTEN. We examined case-control association in 75,238 patients with various types of cancer and 38,297 non-cancer controls, and identified that PTEN pathogenic variants (PVs) were significantly associated with endometrial cancer (OR = 35.7, P = 9.73E-04) and marginally associated with female breast cancer (OR = 19.5, P = 3.92E-03), especially at young onset and with multiple cancers. We observed that among the 127 disease phenotypes the PTEN PV carriers had uterine fibroid, goiter, ovarian cyst, and epilepsy, which is consistent with PTEN-related phenotypes. We also found that weight/height were significantly higher in adult female carriers with PTEN PV (P = 3.1E-04 and P = 0.0014, respectively), which is consistent with overgrowth syndrome of PHTS. Our results indicate the phenotypical features associated with PTEN PVs in a Japanese population, especially female, and can contribute to the screening for PTEN variants and its associated several phenotypes.

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Acknowledgements

This work was supported by RIKEN Junior Research Associate Program (Y.K.). We thank the individuals who participated BioBank Japan. We also acknowledge the staff of the Laboratory for Genotyping Development in RIKEN, the RIKEN-IMS genome platform, and the BioBank Japan project. We are deeply grateful to the late Professor Charis Eng in Cleveland Clinic for her valuable advice on this work and her great contribution to PTEN research. Her memory continues to inspire.

Funding

This work was supported by AMED under Grant Numbers JP19kk0305010, JP20ck0106402, JP19cm0106605, and 20ck0106553.

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Authors and Affiliations

  1. Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Yuki Kanazashi, Shota Sasagawa, Todd A. Johnson, Kazuhiro Maejima & Hidewaki Nakagawa

  2. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Yuki Kanazashi, Naomichi Matsumoto, Yukihide Momozawa & Hidewaki Nakagawa

  3. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Yoshiaki Usui, Yusuke Iwasaki, Mikiko Endo, Mitsuyo Yamaguchi & Yukihide Momozawa

  4. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

    Kouya Shiraishi & Takashi Kohno

  5. Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan

    Teruhiko Yoshida & Kokichi Sugano

  6. Dapartment of Genetic Medicine, Kyoundo Hospital, Sasaki Foundation, Tokyo, Japan

    Kokichi Sugano

  7. Dapartment of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan

    Yoshinori Murakami

  8. Laboratory of Complex Trail Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Yoichiro Kamatani

  9. Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Koichi Matsuda

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  1. Yuki Kanazashi
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  2. Yoshiaki Usui
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Contributions

Y.M.O. and H.N. conceived and designed the study. Y.M.O., Y.M.U., Y.K., and K.M. managed the materials in B.B.J., M.E., Y.I., M.Y., and Y.M.O. produced sequence data, and Y.I. and Y.U. performed data curation. Y.K. performed data analysis and statistical tests. S.S., T.J., and Y.I. assisted the variant annotation and case-control analysis. K.S., T.K., T.Y, and K.S. assisted with the data interpretation. K.S., T.K., and Y.Mo. obtained the funding. Y.K. and H.N. wrote the initial draft of the manuscript. N.M., Y.Mo., and H.N. supervised the study. All authors reviewed this manuscript.

Corresponding authors

Correspondence to Yukihide Momozawa or Hidewaki Nakagawa.

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All participants provided written informed consent. The study was approved by the ethical committees of the Institute of Medical Sciences, University of Tokyo, and RIKEN Center for Integrative Medical Sciences.

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Kanazashi, Y., Usui, Y., Iwasaki, Y. et al. Cancer and disease profiles for PTEN pathogenic variants in Japanese population. J Hum Genet 70, 135–140 (2025). https://doi.org/10.1038/s10038-024-01311-z

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