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. 2021 Jan 28;19(1):46.
doi: 10.1186/s12967-021-02710-y.

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

Heba Alshaker  1 , Robert Mills  2 , Ewan Hunter  3 , Matthew Salter  3 , Aroul Ramadass  3 , Benjamin Matthew Skinner  4 , Willem Westra  3 , Jayne Green  3 , Alexandre Akoulitchev  3 , Mathias Winkler  5 , Dmitri Pchejetski  6
Affiliations

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

Heba Alshaker et al. J Transl Med. .

Abstract

Background: 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. 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.

Methods: In 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.

Results: We 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.

Conclusions: Our results demonstrate specific chromosome conformations in the blood of PCa patients that allow PCa diagnosis and risk stratification with high sensitivity and specificity.

Keywords: Blood test; Diagnosis; Epigenetics; Nucleome; Prognosis; Prostate cancer.

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Conflict of interest statement

Ewan Hunter, Matthew Salter, Aroul Ramadass, Willem Westra, Jayne Green and Alexandre Akoulitchev are employees of Oxford BioDynamics. A. Akoulitchev and A. Ramadass are company directors. Oxford BioDynamics holds patents on the EpiSwitch™ technology. The remaining authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Chromosomal loops structure and conformation assay. a Chromosomal loop contains the enhancer region that increases target gene promoter activity. b During cancer progression there is increased looping in some tumour-related genes leading to abnormal gene expression. c Chromosome conformation assay: DNA is crosslinked, digested, ligated and new sequences (in places where loops were) are predicted using relevance machine vector. Loops presence is then detected using DNA microarray. Resulting markers are analysed using multivariate analysis yielding specific epigenetic signatures for selected patient cohorts
Fig. 2
Fig. 2
Three-step approach to identify, evaluate, and validate diagnostic and prognostic biomarkers for prostate cancer (PCa)
Fig. 3
Fig. 3
Graphical representation of the genomic co-ordinates of the ETS1, MAP3K14, SLC22A3 and CASP2 chromosome conformation signature markers associated with PCa. a The Ensembl browser view of the ETS1, MAP3K14, SLC22A3 and CASP2 genes on chromosomes 11, 17, 6 and 7 with the EpiSwitch™ sites marked with green, pink, blue and red symbols, respectively. b Circos plots of ETS1 (green) MAP3K14 (pink), SLC22A3 (blue) and CASP2 (red) chromosome conformation signature markers showing the chromosomal loop
Fig. 4
Fig. 4
Principal component analysis for the five-markers applied to 78 samples containing two groups. First group, 49 known samples (24 PCa and 25 cancer-free controls (Cntrl)) combined with a second group of 29 samples including, 24 PCa samples and 5 healthy Cntrl samples. PCa samples in green and cancer-free Cntrl samples in red
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