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Cyclin-Dependent Kinase Activity Correlates with the Prognosis of Patients Who Have Gastrointestinal Stromal Tumors

  • Bone and Soft Tissue Sarcomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The estimation of recurrence risk remains a critical issue in relation to gastrointestinal stromal tumors (GISTs) treated with adjuvant therapy. The accuracy of the commonly used risk stratifications is not always adequate.

Methods

For this study, data were prospectively collected from 68 patients with GISTs who underwent R0 surgery between 2004 and 2009. The results from this analysis cohort were evaluated using the data obtained from an additional 40 patients in the validation cohort. Cyclin-dependent kinase 1 (CDK1)- and CDK2-specific activities were measured using a non-RI kinase assay system.

Results

The specific activities of CDK1 and CDK2, but not their expression, significantly correlated with recurrence. The specific activities of both CDK1 and CDK2 were independently correlated with mitosis and significantly correlated with recurrence-free survival (RFS). In the multivariate analysis, CDK2-specific activity (P = 0.0006), tumor size (P = 0.0347), and KIT deletion mutations (P = 0.0006) were significantly correlated with RFS in the analysis cohort. In the validation cohort, CDK2-specific activity (P = 0.0368) was identified as an independent prognostic factor for tumor recurrences with tumor location (P = 0.0442).

Conclusion

The results suggest that the specific activities of CDK1 and CDK2 may reflect the proliferative activity of GISTs and that CDK2-specific activity is a good prognostic factor predicting recurrence after macroscopic complete resection of GISTs.

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Acknowledgment

This study was partly supported by the Sysmex Corporation (Kobe, Japan) and by a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and by the National Cancer Centre Research and Development Fund.

Disclosure

Toshirou Nishida received grants from Novartis and Bayer, and honoraria from Pfizer, Bayer, and Novartis irrelevant to the submitted work. Sysmex Corporation (Kobe, Japan) was involved in the study design as well as measurement of CDK activities and their interpretation. Tomoko Matsushima, Yuko Kawasaki, and Satoshi Nakayama of Sysmex Corporation had analyzed activities of CDKs, and Tomoko Matsushima had access to the full raw data. Hideki Ishihara, previously affiliated with the Sysmex Corporation, was authorized for access to the primary raw data and performed the initial analysis of this study. Currently, Hideki Ishihara and Satoshi Nakayama are affiliated with the other companies, which have no relationship with the Sysmex Corporation. The remaining authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Toshirou Nishida MD, PhD

  2. Department of Surgery, Osaka Police Hospital, Osaka, Japan

    Toshirou Nishida MD, PhD, Takeshi Omori MD, PhD & Shigeyuki Ueshima MD

  3. Department of Pathology, Osaka Police Hospital, Osaka, Japan

    Masahiko Tsujimoto MD, PhD

  4. Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Toshirou Nishida MD, PhD & Tsuyoshi Takahashi MD, PhD

  5. Sysmex Corporation, Kobe, Hyogo, Japan

    Tomoko Matsushima PhD, Yuko Kawasaki PhD, Satoshi Nakayama PhD & Hideki Ishihara PhD

  6. Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan

    Masahiro Yamamura MD

  7. Department of Surgery, Kanagawa Cancer Centre, Yokohama, Kanagawa, Japan

    Haruhiko Cho MD

  8. Department of Surgical Pathology, Hyogo College of Medicine, Kobe, Hyogo, Japan

    Seiichi Hirota MD, PhD

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  1. Toshirou Nishida MD, PhD
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  2. Tomoko Matsushima PhD
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  3. Masahiko Tsujimoto MD, PhD
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  4. Tsuyoshi Takahashi MD, PhD
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  7. Takeshi Omori MD, PhD
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  10. Seiichi Hirota MD, PhD
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  11. Shigeyuki Ueshima MD
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  12. Hideki Ishihara PhD
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Corresponding author

Correspondence to Toshirou Nishida MD, PhD.

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10434_2015_4438_MOESM1_ESM.tif

Supplementary Fig. 1 Patient selection in the analysis and validation cohorts (review only). Supplementary material 1 (TIFF 1115 kb)

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Nishida, T., Matsushima, T., Tsujimoto, M. et al. Cyclin-Dependent Kinase Activity Correlates with the Prognosis of Patients Who Have Gastrointestinal Stromal Tumors. Ann Surg Oncol 22, 3565–3573 (2015). https://doi.org/10.1245/s10434-015-4438-y

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  • DOI: https://doi.org/10.1245/s10434-015-4438-y

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