TY - JOUR
T1 - Cell Cycle Protein Expression in Neuroendocrine Tumors
T2 - Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein with Proliferative Index
AU - Shi, Yan
AU - Qian, Zhi Rong
AU - Zhang, Sui
AU - Li, Wanwan
AU - Masugi, Yohei
AU - Li, Tingting
AU - Chan, Jennifer A.
AU - Yang, Juhong
AU - Da Silva, Annacarolina
AU - Gu, Mancang
AU - Liu, Li
AU - Hamada, Tsuyoshi
AU - Kosumi, Keisuke
AU - Dutton, Trevor
AU - Brais, Lauren K.
AU - Nishihara, Reiko
AU - Fuchs, Charles S.
AU - Ogino, Shuji
AU - Kulke, Matthew H.
N1 - Funding Information:
National Natural Science Foundation of China No.81402016, Beijing Municipal Natural Science Foundation No.7152140 and Beijing Nova Program XXJH2015B098. K.K. is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science. L.L. is supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant from Huazhong University of Science and Technology.
Funding Information:
The authors are grateful the Gitta and Saul Kurlat Fund for Neuroendocrine Tumor Research, Jane Dybowski Fund for Neuroendocrine Cancer, McIntyre Family Fund for Neuroendocrine Tumor Research, Lipson Family Fund, Goldhirsh-Yellin Foundation Fund for Neuroendocrine Tumor Research, and the Murphy Family Fund for Carcinoid Tumor Research.
Funding Information:
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. Received for publication February 3, 2017; accepted September 8, 2017. Address correspondence to: Matthew H. Kulke, MD, MMSc, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave, Boston, MA 02215 (e‐mail: matthew_kulke@dfci.harvard.edu). This work was supported by US National Institutes of Health grants R01 CA151532 to M.H.K.; P50 CA127003 to C.S.F.; R35 CA197735 to S.O.; and K07 CA190673 to R.N. This work was also supported by Medical Oncology Translation Grant from the Department of Medical Oncology, Dana-Farber Cancer Institute to Z.R.Q. Y.S. is supported by the grants from
Publisher Copyright:
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - CCND1
KW - CDK4/CDK6
KW - CDKN1B (p27/Kip1)
KW - neuroendocrine tumors
KW - phospho-RB1
KW - proliferation
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U2 - 10.1097/MPA.0000000000000944
DO - 10.1097/MPA.0000000000000944
M3 - Article
C2 - 28991877
AN - SCOPUS:85032204715
SN - 0885-3177
VL - 46
SP - 1347
EP - 1353
JO - Pancreas
JF - Pancreas
IS - 10
ER -
