Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade

Norimoto Nakamura, Hidetaka Yamamoto, Takashi Yao, Yoshinao Oda, Ken Ichi Nishiyama, Masakazu Imamura, Tomomi Yamada, Hajime Nawata, Masazumi Tsuneyoshi

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Abstract

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (≥5 cm), mitotic counts (≥5/50 high-power fields), Ki-67 LI (≥4.92%), cyclin A LI (≥1.61%), and cdc2 LI (≥1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.

Original languageEnglish
Pages (from-to)828-837
Number of pages10
JournalHuman Pathology
Volume36
Issue number7
DOIs
Publication statusPublished - Jul 1 2005

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Cell Cycle Proteins
Gastrointestinal Stromal Tumors
Cyclin A
Cyclin B1
Disease-Free Survival
Cyclin E
Neoplasms
Cyclin D1
Cell Cycle
Multivariate Analysis
Cell Proliferation
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. / Nakamura, Norimoto; Yamamoto, Hidetaka; Yao, Takashi; Oda, Yoshinao; Nishiyama, Ken Ichi; Imamura, Masakazu; Yamada, Tomomi; Nawata, Hajime; Tsuneyoshi, Masazumi.

In: Human Pathology, Vol. 36, No. 7, 01.07.2005, p. 828-837.

Research output: Contribution to journalArticle

Nakamura, Norimoto ; Yamamoto, Hidetaka ; Yao, Takashi ; Oda, Yoshinao ; Nishiyama, Ken Ichi ; Imamura, Masakazu ; Yamada, Tomomi ; Nawata, Hajime ; Tsuneyoshi, Masazumi. / Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. In: Human Pathology. 2005 ; Vol. 36, No. 7. pp. 828-837.
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abstract = "Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (≥5 cm), mitotic counts (≥5/50 high-power fields), Ki-67 LI (≥4.92{\%}), cyclin A LI (≥1.61{\%}), and cdc2 LI (≥1.25{\%}) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.",
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AU - Oda, Yoshinao

AU - Nishiyama, Ken Ichi

AU - Imamura, Masakazu

AU - Yamada, Tomomi

AU - Nawata, Hajime

AU - Tsuneyoshi, Masazumi

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N2 - Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (≥5 cm), mitotic counts (≥5/50 high-power fields), Ki-67 LI (≥4.92%), cyclin A LI (≥1.61%), and cdc2 LI (≥1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.

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