Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas.

Abstract

PURPOSE:

Small-cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small-cell carcinoma from adenocarcinoma.

EXPERIMENTAL DESIGN:

We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small-cell carcinoma and adenocarcinoma specimens.

RESULTS:

Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small-cell carcinoma from prostatic adenocarcinoma in patient specimens (n = 13 and 9, respectively). At the protein level, cyclin D1, but not p16, was useful to distinguish small-cell carcinoma from adenocarcinoma. Overall, 88% (36/41) of small-cell carcinomas showed cyclin D1 loss by immunostaining compared with 2% (2/94) of Gleason score 7-10 primary adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small-cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death.

CONCLUSIONS:

Cyclin D1 loss identifies prostate tumors with small-cell differentiation and may identify a small subset of adenocarcinomas with poor prognosis. Clin Cancer Res; 21(24); 5619-29. ©2015 AACR.

• Authors: Harrison Tsai, Carlos L Morais, Mohammed Alshalalfa, Hsueh-Li Tan, Zaid Haddad, Jessica Hicks, Nilesh Gupta, Jonathan I Epstein, George J Netto, William B Isaacs, Jun Luo, Rohit Mehra, Robert L Vessella, R Jeffrey Karnes, Edward M Schaeffer, Elai Davicioni, Angelo M De Marzo, Tamara L Lotan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 24 Pg. 5619-29 (Dec 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26246306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Cyclin-Dependent Kinase Inhibitor p16
• Retinoblastoma Protein
• Cyclin D1

Topics

• Adenocarcinoma (diagnosis, genetics, metabolism, mortality, therapy)
• Animals
• Biomarkers, Tumor
• Carcinoma, Small Cell (diagnosis, genetics, metabolism, therapy)
• Cyclin D1 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Disease Models, Animal
• Gene Expression
• Gene Expression Profiling
• Heterografts
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Mice
• Neoplasm Grading
• Neoplasm Metastasis
• Prognosis
• Prostatic Neoplasms (diagnosis, genetics, metabolism, mortality, therapy)
• Retinoblastoma Protein (genetics, metabolism)