title: Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Harrison
authors.initials: H
authors.lastname: Tsai
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Morais
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hsueh-Li
authors.initials: HL
authors.lastname: Tan
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Haddad
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Pathology, Henry Ford Health System, Detroit, Michigan.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schaeffer
authors.affiliation: GenomeDx Biosciences, Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. tlotan1@jhmi.edu.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D000818:Animals; D014408:Biomarkers, Tumor; D018288:Carcinoma, Small Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D019938:Cyclin D1