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Pancreas. 2017 Nov/Dec;46(10):1347-1353. doi: 10.1097/MPA.0000000000000944.

Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index.

Author information

1
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.

Abstract

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.

PMID:
28991877
PMCID:
PMC5645256
DOI:
10.1097/MPA.0000000000000944
[Indexed for MEDLINE]
Free PMC Article

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