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Gastric Cancer

, Volume 22, Issue 6, pp 1100–1108 | Cite as

The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors

  • Yuki Koga
  • Masaaki Iwatsuki
  • Kohei Yamashita
  • Yuki Kiyozumi
  • Junji Kurashige
  • Toshiro Masuda
  • Kojiro Eto
  • Shiro Iwagami
  • Kazuto Harada
  • Takatsugu Ishimoto
  • Yoshifumi Baba
  • Naoya Yoshida
  • Nobutomo Miyanari
  • Hiroshi Takamori
  • Jaffer A. Ajani
  • Hideo BabaEmail author
Original Article
  • 374 Downloads

Abstract

Background

Few reliable prognostic markers have been established despite elucidation of the molecular mechanisms of gastrointestinal stromal tumor (GIST) development. We evaluated F-box and WD repeat domain-containing 7 (FBXW7), a cell-cycle-regulating and tumor suppressor, in GISTs. We aimed to determine the clinical relevance of FBXW7 in GISTs and characterize the molecular mechanism of FBXW7 in a GIST cell line.

Methods

We measured FBXW7 expression in 182 GIST cases, correlated the expression levels with clinicopathological features, and characterized the molecular mechanism underlying suppressed FBXW7 expression in GIST cells in vitro.

Results

Of the 182 GISTs, 98 (53.8%) and 84 (46.2%) were categorized in the high and low FBXW7 expression groups, respectively. Compared with the high FBXW7 expression group, the low expression group showed a significantly poorer prognosis in terms of recurrence-free (P = 0.01) and overall (P = 0.03) survival. FBXW7 expression was a significant independent factor affecting the 10-year recurrence-free survival rate (P = 0.04). In vitro, FBXW7-specific siRNAs enhanced c-myc and Notch 1 protein expression and upregulated cell proliferation, invasion, and migration.

Conclusion

FBXW7 is a potential predictive marker of recurrence after curative resection of GISTs. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely compared with a conventional risk stratification model.

Keywords

Gastrointestinal stromal tumor FBXW7 c-myc Notch 1 High risk 

Notes

Acknowledgements

The authors thank Dr. Takihiro Kamio, Dr. Reiji Muto and Dr. Toshihiko Murayama for providing clinical samples. The authors also thank Dr. Miyake and Ms. Ogata for their excellent technical assistance.

Funding

This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant numbers 16K10463 and 16KK0184).

Compliance with ethical standards

Conflict of interest

We have no conflicts of interest to declare.

Ethics approval and consent to participate

Ethics approval of this study was granted by the ethics committee at Kumamoto University Hospital (approval number 2212) The study was conducted in accordance with the Declaration of Helsinki principles.

Supplementary material

10120_2019_950_MOESM1_ESM.pptx (164 kb)
Supplemental Fig. 1: Kaplan–Meier analysis of recurrence-free and overall survival in 2nd cohort. (a) Recurrence-free survival and (b) overall survival curves based on FBXW7 expression in all GIST cases (n = 51). (c) Recurrence-free survival in the high-risk cases (n = 12) and (d) overall survival curves based on FBXW7 expression in the intermediate-/high-risk cases (n = 23). The high and low FBXW7 expression groups are indicated by the unbroken and broken lines, respectively. Supplemental Fig. 2: Kaplan–Meier analysis of recurrence-free and overall survival based on c-myc, p-c-myc and Notch 1 expression. (a) Recurrence-free survival and (b) overall survival curves based on c-myc, p-c-myc and Notch 1 expression in all GIST cases (n = 182). The high and low c-myc, p-c-myc and Notch 1 expression groups are indicated by the unbroken and broken lines, respectively. (PPTX 164 KB)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Yuki Koga
    • 1
  • Masaaki Iwatsuki
    • 1
    • 2
  • Kohei Yamashita
    • 1
  • Yuki Kiyozumi
    • 1
  • Junji Kurashige
    • 3
  • Toshiro Masuda
    • 4
  • Kojiro Eto
    • 1
  • Shiro Iwagami
    • 1
  • Kazuto Harada
    • 1
    • 2
  • Takatsugu Ishimoto
    • 1
  • Yoshifumi Baba
    • 1
  • Naoya Yoshida
    • 1
  • Nobutomo Miyanari
    • 3
  • Hiroshi Takamori
    • 4
  • Jaffer A. Ajani
    • 2
  • Hideo Baba
    • 1
    Email author
  1. 1.Department of Gastroenterological Surgery, Graduate School of Life SciencesKumamoto UniversityKumamotoJapan
  2. 2.Department of Gastrointestinal Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of SurgeryNational Hospital Organization Kumamoto Medical CenterKumamotoJapan
  4. 4.Department of SurgerySaiseikai Kumamoto HospitalKumamotoJapan

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