Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index.
Shi, Yan MD, PhD *+++; Qian, Zhi Rong MD, PhD *++; Zhang, Sui MS *; Li, Wanwan MD *++; Masugi, Yohei MD, PhD *++; Li, Tingting MD, PhD *; Chan, Jennifer A. MD, PhD *; Yang, Juhong MD, PhD *[S]; Da Silva, Annacarolina MD, PhD *++; Gu, Mancang PhD *++[//]; Liu, Li PhD *++[P]#; Hamada, Tsuyoshi MD, PhD *++; Kosumi, Keisuke MD, PhD *++; Dutton, Trevor MD, PhD *; Brais, Lauren K. MPH *; Nishihara, Reiko PhD *[P]#**++++++; Fuchs, Charles S. MD, MPH [S][S][//][//][P][P]##; Ogino, Shuji MD, PhD, MS *++++++++; Kulke, Matthew H. MD, MMsc *
46(10):1347-1353, November/December 2017.
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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.
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