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Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.

ABSTRACT: Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Despite this loss, high-grade tumours exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory programme. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumours. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumours, critical for molecular stratification of the disease.

SUBMITTER: Eksi SE

PROVIDER: S-EPMC8674326 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.

Eksi Sebnem Ece SE Chitsazan Alex A Sayar Zeynep Z Thomas George V GV Fields Andrew J AJ Kopp Ryan P RP Spellman Paul T PT Adey Andrew C AC

Nature communications 20211215 1

Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Des ...[more]

PMID: 34911933

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Project description:BackgroundThe consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown.ObjectiveTo evaluate the clinical implications and genomic features of low-PSA, high-grade disease.Design, setting, and participantsThis was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1-4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004-2017.Outcome measurements and statistical analysisMultivariable Fine-Gray and Cox regressions were used to analyze prostate cancer-specific mortality (PCSM) and all-cause mortality, respectively.Results and limitationsFor Gleason 8-10 disease, using PSA 4.1-10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6-4.0 (n=4199), 10.1-20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1-10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA ≤2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6-4.0 (n=54 152), 10.1-20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (pinteraction<0.001). Gleason 8-10, PSA ≤2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8-10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not ≤2.5ng/ml (AHR 1.36; p=0.084; pinteraction=0.021). For Gleason 8-10 tumors, PSA ≤2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason ≤7 disease.ConclusionsLow-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.Patient summaryIn this study, we found that low-prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.

Dataset Information

Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.

Publications

Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.

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