Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post‐radiotherapy, and those with de novo metastatic disease

Author:

Charlton Philip Vincent12,O'Reilly Dawn1,Philippou Yiannis3,Rao Srinivasa Rao4,Lamb Alastair David Gordon34,Mills Ian Geoffrey4ORCID,Higgins Geoff Stuart12,Hamdy Freddie Charles34,Verrill Clare45,Buffa Francesca Meteora1,Bryant Richard John34ORCID

Affiliation:

1. Department of Oncology University of Oxford Oxford UK

2. Department of Oncology Oxford University Hospitals NHS Foundation Trust Oxford UK

3. Department of Urology Oxford University Hospitals NHS Foundation Trust Oxford UK

4. Nuffield Department of Surgical Sciences University of Oxford Oxford UK

5. Department of Pathology Oxford University Hospitals NHS Foundation Trust Oxford UK

Abstract

AbstractBackgroundIt is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin‐fixed paraffin‐embedded (FFPE) prostate biopsies from cohorts with post‐radiotherapy (RT) long‐term clinical follow‐up has been limited. Utilizing parallel sequencing modalities, we performed a proof‐of‐principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with (i) stable PCa (sPCa) postprimary or salvage RT, (ii) progressing PCa (pPCa) post‐RT, and (iii) de novo metastatic PCa (mPCa).MethodsA cohort of 19 patients with diagnostic prostate biopsies (n = 6 sPCa, n = 5 pPCa, n = 8 mPCa) and mean 4 years 10 months follow‐up (diagnosed 2009–2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3′RNA sequencing (3′RNAseq) (n = 19), nanoString analysis (n = 12), and Illumina 850k methylation (n = 8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes and methylated genomic regions (MGRs).ResultsEighteen of 19 samples provided useable 3′RNAseq data. Principal component analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ~600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression‐free survival post‐RT (p < 0.0001) in an external cohort.Conclusions3′RNAseq, nanoString and 850k‐methylation analyses are each achievable from historical FFPE diagnostic pretreatment prostate biopsies, unlocking the potential to utilize large cohorts of historic clinical samples. Profiling similarities between individuals with pPCa and mPCa suggests biological similarities and historical radiological staging limitations, which warrant further investigation.

Publisher

Wiley

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