Abstract
BackgroundIntratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies.Patients and methodsForty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification.ResultsWe demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of β-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of β-catenin. Analysis of all patients with activating Wnt/β-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion.ConclusionsThe PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/β-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies.Clinical Trials.gov IdentifierNCT02022371
Highlights
Prostate cancer (PC) is the second most common malignancy in men with an incidence of 1.1 million men per year leading to an estimated 307,000 deaths worldwide [1]
In-depth exploration of genomic Intratumoural heterogeneity (ITH) with multiregion sequencing (M-Seq) in the primary PC has relied on prostatectomy patient series [9, 10] to provide good-quality tissue; this has enriched for clinically low- and intermediate-risk disease [5, 6]
To explore the relative frequency of somatic nucleotide variations (SNV) and somatic copy number alterations (SCNAs) in mHNPC and hrlPC, we focused on driver genes identified in previous PC series (Figure 2) [16, 17]
Summary
Prostate cancer (PC) is the second most common malignancy in men with an incidence of 1.1 million men per year leading to an estimated 307,000 deaths worldwide [1]. Accurate risk stratification has been confounded by underestimation of disease burden using standard transrectal ultrasound-guided biopsies and extensive tumour heterogeneity of primary PC [4,5,6]. A recent improvement on transrectal ultrasound-guided biopsies is targeted magnetic resonance imaging (MRI)-guided biopsies that increase the likelihood of sampling clinically significant disease [7]. Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies
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