title: Expression level of the mitotic checkpoint protein and G2-M cell cycle regulators and prognosis in gastrointestinal stromal tumors in the stomach.
abstract: The biological behavior of gastrointestinal stromal tumors (GISTs) ranges from benign to malignant, and the risk of an adverse outcome is correlated with the location of the primary tumor, tumor size, and mitotic counts. Cell cycle regulators are potentially associated with the tumorigenesis and progression of GISTs. Checkpoint with forkhead and ring finger (CHFR) functions as an important checkpoint protein in the early to mid-prophase to regulate mitosis. In this study, we evaluated the expression of CHFR and several cell cycle regulators, including cyclin A, cyclin B1, cdc2, and cdk2, by immunohistochemical staining in 53 cases of primary gastric GISTs, and compared the immunohistochemical results with the clinicopathological factors or the GIST risk grades as modified by Miettinen et al. Of the 53 cases, 18 (34%) showed decreased nuclear CHFR expression. Decreased CHFR expression was correlated with higher mitotic counts [>5/50 high-power fields (HPFs)] (p = 0.039) and a high-risk grade (p = 0.0475), but not with expression of other cell cycle regulators. Higher cyclin A labeling index (LI, >1.5%), cyclin B1 LI (>0.25%), cdc2 LI (>1.16%), Ki-67 LI (>4.9%), mitotic counts (>5/50 HPF) and high-risk grade were each associated with shorter disease-free survival (p = 0.0017, p = 0.003, p = 0.0471, p = 0.002, p < 0.001, and p = 0.0017, respectively). Our results suggest that modified risk grade and increased expression of G2-M regulators such as cyclin A, cyclin B1, and cdc2 are useful for predicting the biological behavior of gastric GISTs. In addition, decreased CHFR expression may play a role in increased proliferative activity of higher grade GISTs.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Fujita
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.forename: Norimoto
authors.initials: N
authors.lastname: Nakamura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tsuneyoshi
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D016016:Proportional Hazards Models; D044767:Ubiquitin-Protein Ligases
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases