title: Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas.
abstract: We have described a rare group of prostate adenocarcinomas that show aberrant expression of p63, a protein strongly expressed in prostatic basal cells and absent from usual-type acinar prostate cancers. The partial basal-like immunophenotype of these tumors is intriguing in light of the persistent debate surrounding the cell-of-origin for prostate cancer; however, their molecular phenotype is unknown. We collected 37 of these tumors on radical prostatectomy and biopsy and assessed subsets for a diverse panel of molecular markers. The majority of p63-expressing tumors were positive for the ΔNp63 isoform (6/7) by immunofluorescence and p63 mRNA (7/8) by chromogenic in situ hybridization. Despite p63 positivity, these tumors uniformly expressed luminal-type cytokeratin proteins such as CK18 (13/13), CK8 (8/8), and markers of androgen axis signaling commonly seen in luminal cells, including androgen receptor (10/11), NKX3.1 (8/8), and prostein (12/13). Conversely, basal cytokeratins such as CK14 and CK15 were negative in all cases (0/8) and CK5/6 was weakly and focally positive in 36% (4/11) of cases. Pluripotency markers including β-catenin, Oct4, and c-kit were negative in p63-expressing tumors (0/11). Despite nearly universal expression of androgen receptor and downstream androgen signaling targets, p63-expressing tumors lacked ERG rearrangements by fluorescence in situ hybridization (0/14) and ERG protein expression (0/37). No tumors expressed SPINK1 or showed PTEN protein loss (0/19). Surprisingly, 74% (14/19) of p63-expressing tumors expressed GSTP1 protein at least focally, and 33% (2/6) entirely lacked GSTP1 CpG island hypermethylation by bisulfite sequencing. In contrast to usual prostatic adenocarcinomas, prostate tumors with p63 expression show a mixed luminal/basal immunophenotype, uniformly lack ERG gene rearrangement, and frequently express GSTP1. These data strongly suggest that p63-expressing prostate tumors represent a molecularly distinct subclass and further study of this rare tumor type may yield important insights into the role of p63 in prostatic biology and the prostate cancer cell-of-origin.
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Hsueh-Li
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Haffner
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Esopi
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Vaghasia
authors.affiliation: Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Giovanna A
authors.initials: GA
authors.lastname: Giannico
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Ross
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Pathology, El Camino Hospital, Mountain View, CA, USA.
authors.forename: Ankur R
authors.initials: AR
authors.lastname: Sangoi
authors.affiliation: Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.affiliation: Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Adeboye O
authors.initials: AO
authors.lastname: Osunkoya
authors.affiliation: 1] Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA [2] Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA [3] Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: 1] Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA [2] Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA [3] Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.affiliation: 1] Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA [2] Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; D020033:Protein Isoforms