Integrated multi-omics assessment of lineage plasticity in a prostate cancer patient with brain and dural metastases

Abstract

Metastases to the brain are rare in prostate cancer. Here, we describe a patient with two treatment-emergent metastatic lesions, one to the brain with neuroendocrine prostate cancer (NEPC) histology and one to the dural membrane of adenocarcinoma histology. We performed genomic, transcriptomic, and proteomic characterization of these lesions and the primary tumor to investigate molecular features promoting these metastases. The two metastatic lesions had high genomic similarity, including TP53 mutation and PTEN deletion, with the most striking difference being the additional loss of RB1 in the NEPC lesion. Interestingly, the dural lesion expressed both androgen receptor and neuroendocrine markers, suggesting amphicrine carcinoma (AMPC). When analyzing pioneer transcription factors, the AMPC lesion exhibited elevated FOXA1 activity while the brain NEPC lesion showed elevated HOXC10, NFYB, and OTX2 expression suggesting novel roles in NEPC formation or brain tropism. Our results highlight the utility of performing multi-omic characterization, especially in rare cancer subtypes.

Fig. 1. Patient and biopsy characteristics and genomic features.

a A timeline for the patient from diagnosis to death, with treatment and PSA levels indicated. The staining features are summarized from IHC staining in (c). Created with Biorender.com. b Brain MRI scan (T1- and T2-weighted images after gadolinium contrast) showed lobulated enhancing, expansile intraosseous lesions in the posterior left parietal bone, conglomerated in appearance and measuring ~5.1 × 1.6 cm. There is cortical destruction of the inner and outer tables of the calvarium. There is mass effect on the underlying dura with associated thickening and enhancement. Anteriorly, one of these enhancing components infiltrates the adjacent left occipital brain parenchyma (red arrow) and results in a 3.3 cm round-shaped intraparenchymal hemorrhage with surrounding vasogenic edema and mass affect. There is a second dural-based 1.2 × 1.4 cm metastatic focus (green arrow) next to left posterior temporal lobe with suspicion of adjacent brain parenchyma invasion. The cerebral ventricles are proportionate to the sulci, without midline shift. c Top H&E: Grade Group 5 acinar adenocarcinoma (black arrows) infiltrating prostate stroma and surrounding normal glands (blue arrow). Gleason pattern 4 carcinoma was also present (not shown). Middle H&E: Cribriform acinar adenocarcinoma involving the peridural connective tissue. Bottom H&E: Underlying high-grade neuroendocrine carcinoma (NEPC) with sheet-like growth pattern and high mitotic activity replacing brain parenchyma. Staining for AR, TP53, INSM1, CHGA, and PD-L1 is shown. The black arrow in TP53 for the dura adenocarcinoma is a focal area of staining suggestive of mutated pattern of TP53, as similar to TP53 in the NEPC component. The black arrow in PD-L1indicates low (5%) staining in the dural adenocarcinoma. d Genes of interest in prostate cancer with their most significant functional impact as calculated by variant effect predictor (VEP) consequences, indicated by color. e Heatmap of log2 copy ratio of dura adenocarcinoma or brain NEPC as compared to primary prostate.

Fig. 2. AR and NE features distinguish sample subtypes.

Heatmap of transcriptome (a) and proteome (b) with unsupervised hierarchical clustering. c Heatmap of normalized enrichment scores from GSEA analysis, with significance marked (*FDR < 0.05, **FDR < 0.01, ***FDR < 0.001, ****FDR < 0.0001). d Heatmap of protein expression of genes in Hallmark pathways identified in (c). Panel of AR- and NE-associated genes and the difference of expression in transcriptome (e) and proteome (f) in the metastatic dura adenocarcinoma or metastatic brain neuroendocrine samples from the primary prostate. Error bars indicate standard error of the mean. Heatmap of AR activity (g) or NE activity (h) genes in the transcriptome, with the summative z-score calculation for each sample.

Fig. 3. Transcription factor reprogramming of prostate cancer subtypes.

a Luminal score based on transcript expression using scaled summative z-score. b Neuroendocrine score based on transcript expression using Pearson correlation. c Heatmap of transcriptome expression of pioneer transcription factors. Log2 fold changes in the transcriptome (d) and proteome (e) of transcription factors from (c) and four CRPC subtype classifications CRPC-AR, -NE, -WNT (Wnt signaling), or -SCL (stem cell-like) (Supplementary Fig 4). Heatmaps of transcriptome and proteome as indicated of predicted FOXA1 (f) or NFYB (g) direct targets with summative z-scores indicated.