title: A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis.
abstract: A large number of biological factors that seem to have important prognostic significance have been identified in non-small cell lung cancers (NSCLCs). In the present study, we have characterized expression of cyclin D1 and cyclin E in a cohort of 217 resected NSCLCs from a single institution by immunohistochemistry to analyze their expression in relation to the growth fraction determined by Ki-67 and to prognosis, and then we have constructed a risk-stratification model of cancer death by multiple biological factors in p-stage I NSCLCs. The cyclin E labeling index (LI) was significantly associated with the Ki-67 LI (r = 0.45; P < 0.001). Tumors having high-level cyclin E expression (cyclin E LI > or =30%) showed a significantly higher Ki-67 LI than tumors having low-level cyclin E expression (cyclin E LI <30%; P < 0.001), whereas positive or negative cyclin D1 expression was not associated with the Ki-67 LI (P = 0.1). Cyclin E expression was a significant and independent unfavorable prognostic factor (hazards ratio = 2.09; P = 0.03), as reported previously (Clin. Cancer Res., 6: 11-16, 2000), whereas cyclin D1 expression was not. These findings indicate different roles of cyclin D1 and cyclin E in cell proliferation and in the prognosis of NSCLCs. Furthermore, we stratified this cohort of p-stage I NSCLCs into different survival groups by using biological factors, including cyclin E, Ki-67, and ras p21, which previously we have found to be independent prognostic factors among 10 factors studied in p-stage I NSCLCs. Four groups of patients with markedly different survivals were identified with 5-year survival rates that ranged from 96% for patients with no factors altered to 41% for patients with all three factors altered (P < 0.001). This combination of biological factors was a significant and independent prognostic factor (hazards ratio = 7.94; P = 0.001).
authors: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan. hdakita@med.hokudai.ac.jp
authors: H
authors: H
authors: Dosaka-Akita
authors: F
authors: F
authors: Hommura
authors: T
authors: T
authors: Mishina
authors: S
authors: S
authors: Ogura
authors: M
authors: M
authors: Shimizu
authors: H
authors: H
authors: Katoh
authors: Y
authors: Y
authors: Kawakami
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D015331:Cohort Studies; D019938:Cyclin D1 / Q000096:biosynthesis / Q000502:physiology*; D019927:Cyclin E / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000502:physiology*; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D019927:Cyclin E; D019394:Ki-67 Antigen; D019938:Cyclin D1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)