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

Yan Shi, Zhi Rong Qian, Sui Zhang, Wanwan Li, Yohei Masugi, Tingting Li, Jennifer A. Chan, Juhong Yang, Annacarolina Da Silva, Mancang Gu, Li Liu, Tsuyoshi Hamada, Keisuke Kosumi, Trevor Dutton, Lauren K. Brais, Reiko Nishihara, Charles S. Fuchs, Shuji Ogino, Matthew H. Kulke

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1347-1353
Number of pages7
JournalPancreas
Volume46
Issue number10
DOIs
Publication statusPublished - 2017 Nov 1
Externally publishedYes

Fingerprint

Retinoblastoma Protein
Cell Cycle Proteins
Neuroendocrine Tumors
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p27
Cyclins
Survival
Cyclin D1
Confidence Intervals
Mutation
Neoplasms
Proteins

Keywords

  • CCND1
  • CDK4/CDK6
  • CDKN1B (p27/Kip1)
  • neuroendocrine tumors
  • phospho-RB1
  • proliferation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

Cite this

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

In: Pancreas, Vol. 46, No. 10, 01.11.2017, p. 1347-1353.

Research output: Contribution to journalArticle

Shi, Y, Qian, ZR, Zhang, S, Li, W, Masugi, Y, Li, T, Chan, JA, Yang, J, Da Silva, A, Gu, M, Liu, L, Hamada, T, Kosumi, K, Dutton, T, Brais, LK, Nishihara, R, Fuchs, CS, Ogino, S & Kulke, MH 2017, 'Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein with Proliferative Index', Pancreas, vol. 46, no. 10, pp. 1347-1353. https://doi.org/10.1097/MPA.0000000000000944
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. / Cell Cycle Protein Expression in Neuroendocrine Tumors : Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein with Proliferative Index. In: Pancreas. 2017 ; Vol. 46, No. 10. pp. 1347-1353.
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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.",
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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.

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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