Chromatin conformation changes in peripheral blood can detect prostate cancer and stratify disease risk groups

Heba Alshaker,Robert Mills,Matthew Salter,Ewan Hunter,Dmitri Pchejetski,Jayne Green,Alexandre Akoulitchev,Willem Westra,Aroul Ramadass,Mathias Winkler,Benjamin Matthew Skinner

doi:10.1186/s12967-021-02710-y

Abstract

BackgroundCurrent diagnostic blood tests for prostate cancer (PCa) are unreliable for the early stage disease, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance of negative biopsies in men with PCa. Predicting the risk of PCa is pivotal for making an informed decision on treatment options as the 5-year survival rate in the low-risk group is more than 95% and most men would benefit from surveillance rather than active treatment. Three-dimensional genome architecture and chromosome structures undergo early changes during tumourigenesis both in tumour and in circulating cells and can serve as a disease biomarker.MethodsIn this prospective study we screened whole blood of newly diagnosed, treatment naïve PCa patients (n = 140) and cancer-free controls (n = 96) for the presence of 14,241 chromosomal loops in the loci of 425 genes.ResultsWe have detected specific chromosome conformation changes in the loci of ETS1, MAP3K14, SLC22A3 and CASP2 genes in peripheral blood from PCa patients yielding PCa detection with 80% sensitivity and 80% specificity. Further analysis between PCa risk groups yielded prognostic validation sets consisting of HSD3B2, VEGFC, APAF1, BMP6, ERG, MSR1, MUC1, ACAT1 and DAPK1 genes that achieved 80% sensitivity and 93% specificity stratifying high-risk category 3 vs low risk category 1 and 84% sensitivity and 89% specificity stratifying high risk category 3 vs intermediate risk category 2 disease.ConclusionsOur results demonstrate specific chromosome conformations in the blood of PCa patients that allow PCa diagnosis and risk stratification with high sensitivity and specificity.

Highlights

Current diagnostic blood tests for prostate cancer (PCa) are unreliable for the early stage disease, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance of negative biopsies in men with PCa
A number of more specific blood tests are emerging for PCa detection including 4 K blood test (AUC 0.8) and PHI blood test (90% sensitivity, 17% specificity) [11]
prostate specific antigen (PSA) levels, clinical disease stage and Gleason score are used to establish the severity of PCa and stratify patients to risk groups [13]

Summary

Introduction

Current diagnostic blood tests for prostate cancer (PCa) are unreliable for the early stage disease, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance of negative biopsies in men with PCa. In early PCa, PSA testing is not specific enough to differentiate between early-stage invasive cancers and latent, non-lethal tumours that might otherwise have remained asymptomatic during a man’s lifetime. A number of more specific blood tests are emerging for PCa detection including 4 K blood test (AUC 0.8) and PHI blood test (90% sensitivity, 17% specificity) [11] Both PHI and 4 K tests have a proposed prognostic value [12], its utility is limited [13] and it is currently not widely used in clinical practice. PSA levels, clinical disease stage and Gleason score are used to establish the severity of PCa and stratify patients to risk groups [13]. There is no prognostic blood test available that allows differentiation between low- and high-risk PCa

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