神经内分泌肿瘤中的细胞周期蛋白表达：细胞周期蛋白依赖性激酶4/细胞周期蛋白依赖性激酶6、细胞周期蛋白D1和磷酸化视网膜母细胞瘤蛋白与增殖指数的关联
Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index.
作者信息
Shi Yan, Qian Zhi Rong, Zhang Sui, Li Wanwan, Masugi Yohei, Li Tingting, Chan Jennifer A, Yang Juhong, Da Silva Annacarolina, Gu Mancang, Liu Li, Hamada Tsuyoshi, Kosumi Keisuke, Dutton Trevor, Brais Lauren K, Nishihara Reiko, Fuchs Charles S, Ogino Shuji, Kulke Matthew H
机构信息
From the *Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; †Medical Oncology Department 2, Chinese PLA General Hospital, Beijing, China; ‡Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA; §Collaborative Innovation Center of Tianjin for Medical Epigenetic, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin; ∥College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China; ¶Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; #Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China; **Department of Epidemiology, Harvard T.H. Chan School of Public Health; ††Department of Biostatistics, Harvard T.H. Chan School of Public Health; ‡‡Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School; §§Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; ∥∥Yale Cancer Center; ¶¶Department of Medicine, Yale University School of Medicine; and ##Smilow Cancer Hospital, New Haven, CT.
出版信息
Pancreas. 2017 Nov/Dec;46(10):1347-1353. doi: 10.1097/MPA.0000000000000944.
OBJECTIVES
Dysregulation of the cell cycle has been observed and implicated as an etiologic factor in a range of human malignancies, but remains relatively unstudied in neuroendocrine tumors (NETs). We evaluated expression of key proteins involved in cell cycle regulation in a large cohort of NETs.
METHODS
We evaluated immunohistochemical expression of CDKN1B, CDKN1A, CDKN2A, CDK2, CDK4, CDK6, cyclin D1, cyclin E1, and phosphorylated retinoblastoma protein (phospho-RB1) in a cohort of 267 patients with NETs. We then explored associations between cell cycle protein expression, mutational status, histologic features, and overall survival.
RESULTS
We found that high expression of CDK4, CDK6, CCND1, and phospho-RB1 was associated with higher proliferative index, as defined by MKI67. We additionally observed a trend toward shorter overall survival associated with low expression of CDKN1B. This association seemed strongest in SINETs (multivariate hazards ratio, 2.04; 95% confidence interval, 1.06-3.93; P = 0.03). We found no clear association between CDKN1B mutation and protein expression.
CONCLUSIONS
Our results suggest that dysregulation and activation of the CDK4/CDK6-CCND1-phospho-RB1 axis is associated with higher proliferative index in NETs. Investigation of the therapeutic potential of CDK4/CDK6 inhibitors in higher grade NETs is warranted.
目的
细胞周期失调已被观察到，并被认为是一系列人类恶性肿瘤的病因，但在神经内分泌肿瘤（NETs）中仍相对未被研究。我们评估了一大群NETs中参与细胞周期调控的关键蛋白的表达。
方法
我们评估了267例NETs患者队列中CDKN1B、CDKN1A、CDKN2A、CDK2、CDK4、CDK6、细胞周期蛋白D1、细胞周期蛋白E1和磷酸化视网膜母细胞瘤蛋白（磷酸化RB1）的免疫组化表达。然后，我们探讨了细胞周期蛋白表达、突变状态、组织学特征和总生存期之间的关联。
结果
我们发现，CDK4、CDK6、CCND1和磷酸化RB1的高表达与由MKI67定义的较高增殖指数相关。我们还观察到CDKN1B低表达与总生存期缩短的趋势。这种关联在小肠神经内分泌肿瘤（SINETs）中似乎最强（多变量风险比，2.04；95%置信区间，1.06 - 3.93；P = 0.03）。我们未发现CDKN1B突变与蛋白表达之间存在明确关联。
结论
我们的结果表明，CDK4/CDK6 - CCND1 - 磷酸化RB1轴的失调和激活与NETs中较高的增殖指数相关。有必要研究CDK4/CDK6抑制剂在高级别NETs中的治疗潜力。
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