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Peer-reviewedCC BY-NC-ND 4.0ESMO Open

Identification and prognostic value of non-hotspot POLE exonuclease domain mutations in endometrial cancer

  • T. Kawai1,2
  • H. Yoshida3
  • M. Kobayashi Kato1,4
  • M. Yamaguchi1,2
  • T. Shiraishi1,4,5
  • H. Okada6
  • T. Kondo6
  • T. Koyama7
  • D. Higuchi1,8
  • T. Harazawa1,8
  • A. Ikki1,9,10
  • T. Yamanaka11
15 more authors
  • A. Tateishi12
  • M. Komatsu13,14
  • R. Hamamoto13,14
  • A. Kuchiba15,16
  • T. Shibata15,17
  • J. Nishino18
  • W. Yamagami5
  • K. Matsumoto8
  • T. Kato4
  • T. Kohno1
  • E. Yoshida2,19
  • Y. Terao2
  • K. Yonemori11
  • M. Ishikawa4
  • K. Shiraishi1,10
19 affiliations
  1. 1Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
  2. 2Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
  3. 3Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
  4. 4Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan
  5. 5Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
  6. 6Medical & Biological Laboratories Co, Ltd (MBL), Tokyo, Japan
  7. 7Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
  8. 8Department of Obstetrics and Gynecology, Showa Medical University School of Medicine, Tokyo, Japan
  9. 9Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan
  10. 10Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
  11. 11Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
  12. 12Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
  13. 13Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
  14. 14AI Medical Engineering Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
  15. 15Division of Biostatistical Research, National Cancer Center Institute of Cancer Control, Tokyo, Japan
  16. 16Teikyo University Graduate School of Public Health, Tokyo, Japan
  17. 17Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan
  18. 18Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
  19. 19Department of Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
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Abstract

Background: Endometrial cancer with somatic POLE exonuclease domain mutations (EDMs) has a highly favorable prognosis; however, the clinical implications of non-hotspot EDMs in POLE remain unclear.

Materials and methods: In 793 patients with endometrial cancer enrolled at the National Cancer Center and Juntendo University Hospitals, 25 prespecified variants were screened using the Luminex assay. Whole-exome sequencing (WES) was carried out to evaluate 54 patients with hotspot and non-hotspot EDMs. In patients with endometrial cancer (n = 4864) registered in Genomics Evidence Neoplasia Information Exchange (GENIE), those harboring hotspot EDMs were matched with randomly sampled patients without EDMs, and a polymerase epsilon (POLE) score for gene panel testing was developed.

Results: In our cohort, POLE-EDMs, including hotspot (n = 91) and non-hotspot (n = 12) EDMs, were identified in 103 (12.9%) of 793 patients. The prevalence of grade 3 and advanced-stage endometrial cancer was higher in patients with non-hotspot EDMs than in those with hotspot EDMs. WES analysis of 54 patients revealed no significant differences in genomic mutations between the groups, and four non-hotspot EDMs were identified. A POLE-specific mutational signature was observed in tumors with EDM. In addition, the POLE score criteria were developed based on hotspot EDMs using the GENIE cohort, achieving a detection sensitivity of 0.94. Using the established POLE score, we identified nine non-hotspot EDMs.

Conclusions: We identified 13 novel candidate non-hotspot EDMs using a newly established POLE score for gene panels and demonstrated an association between non-hotspot EDMs and favorable prognosis. The identification of additional non-hotspot EDMs will facilitate precise molecular classification of endometrial cancer.

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Cite

BibTeXRIS
BibTeX
@article{kawai2026identification,
  title = {{Identification and prognostic value of non-hotspot POLE exonuclease domain mutations in endometrial cancer}},
  author = {T. Kawai and H. Yoshida and M. Kobayashi Kato and M. Yamaguchi and T. Shiraishi and H. Okada and T. Kondo and T. Koyama and D. Higuchi and T. Harazawa and A. Ikki and T. Yamanaka and A. Tateishi and M. Komatsu and R. Hamamoto and A. Kuchiba and T. Shibata and J. Nishino and W. Yamagami and K. Matsumoto and T. Kato and T. Kohno and E. Yoshida and Y. Terao and K. Yonemori and M. Ishikawa and K. Shiraishi},
  journal = {ESMO Open},
  year = {2026},
  month = oct,
  doi = {10.1016/j.esmoop.2026.108605},
  url = {https://doi.org/10.1016/j.esmoop.2026.108605},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Identification and prognostic value of non-hotspot POLE exonuclease domain mutations in endometrial cancer
AU  - T. Kawai
AU  - H. Yoshida
AU  - M. Kobayashi Kato
AU  - M. Yamaguchi
AU  - T. Shiraishi
AU  - H. Okada
AU  - T. Kondo
AU  - T. Koyama
AU  - D. Higuchi
AU  - T. Harazawa
AU  - A. Ikki
AU  - T. Yamanaka
AU  - A. Tateishi
AU  - M. Komatsu
AU  - R. Hamamoto
AU  - A. Kuchiba
AU  - T. Shibata
AU  - J. Nishino
AU  - W. Yamagami
AU  - K. Matsumoto
AU  - T. Kato
AU  - T. Kohno
AU  - E. Yoshida
AU  - Y. Terao
AU  - K. Yonemori
AU  - M. Ishikawa
AU  - K. Shiraishi
PY  - 2026
DA  - 2026/10/29
JO  - ESMO Open
DO  - 10.1016/j.esmoop.2026.108605
UR  - https://doi.org/10.1016/j.esmoop.2026.108605
AB  - Background: Endometrial cancer with somatic POLE exonuclease domain mutations (EDMs) has a highly favorable prognosis; however, the clinical implications of non-hotspot EDMs in POLE remain unclear.  Materials and methods: In 793 patients with endometrial cancer enrolled at the National Cancer Center and Juntendo University Hospitals, 25 prespecified variants were screened using the Luminex assay. Whole-exome sequencing (WES) was carried out to evaluate 54 patients with hotspot and non-hotspot EDMs. In patients with endometrial cancer (n = 4864) registered in Genomics Evidence Neoplasia Information Exchange (GENIE), those harboring hotspot EDMs were matched with randomly sampled patients without EDMs, and a polymerase epsilon (POLE) score for gene panel testing was developed.  Results: In our cohort, POLE-EDMs, including hotspot (n = 91) and non-hotspot (n = 12) EDMs, were identified in 103 (12.9%) of 793 patients. The prevalence of grade 3 and advanced-stage endometrial cancer was higher in patients with non-hotspot EDMs than in those with hotspot EDMs. WES analysis of 54 patients revealed no significant differences in genomic mutations between the groups, and four non-hotspot EDMs were identified. A POLE-specific mutational signature was observed in tumors with EDM. In addition, the POLE score criteria were developed based on hotspot EDMs using the GENIE cohort, achieving a detection sensitivity of 0.94. Using the established POLE score, we identified nine non-hotspot EDMs.  Conclusions: We identified 13 novel candidate non-hotspot EDMs using a newly established POLE score for gene panels and demonstrated an association between non-hotspot EDMs and favorable prognosis. The identification of additional non-hotspot EDMs will facilitate precise molecular classification of endometrial cancer.
SN  - 2059-7029
ER  -