Genomic Characterization of Prostatic Basal Cell Carcinoma

Abstract

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.

Figure 1

A: Hematoxylin and eosin–stained micrograph showing histomorphologic features of case 1. Note the nuclear atypia and dense desmoplastic response in this case. B: Table listing consensus single-nucleotide variants as well as insertions and deletions. C: Copy number profile highlights copy number losses (green) that affect chromosomes 5, 13, 14, and 16. Dots represent normalized log ratios for 10-kb windows. Blue indicates copy neutral; green, copy number loss. Scale bar = 50 μm (A).

Figure 2

A: Hematoxylin and eosin–stained micrograph showing histomorphologic features of case 2. Note the cribriform-like growth pattern with abundant eosinophilic basement membrane material that resembles cylindromas of the skin. B: Table listing consensus single-nucleotide variants (SNVs) and insertions and deletions. C: Copy number profile highlights copy number loss (green) affecting chromosome 16. Dots represent normalized log ratios for 10-kb windows. Blue indicates copy neutral; green, copy number loss. Scale bar = 50 μm (A).

Figure 3

A: Western blot analysis of benign basal-like prostate epithelial cells stably transduced with nontargeting control vectors [short hairpin control (sh-Ctrl)] and CYLD targeting shRNAs [short hairpin CYLD (sh-CYLD)] demonstrate effective depletion of CYLD protein levels. B: Cell proliferation assessment based on cellular confluency determined by live cell imaging of sh-CYLD and sh-Ctrl cells. ∗P < 0.01. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.