Abstract
BackgroundHuman prostate cancers display numerous DNA methylation changes compared to normal tissue samples. However, definitive identification of features related to the cells’ malignant status has been compromised by the predominance of cells with luminal features in prostate cancers.MethodsWe generated genome-wide DNA methylation profiles of cell subpopulations with basal or luminal features isolated from matched prostate cancer and normal tissue samples.ResultsMany frequent DNA methylation changes previously attributed to prostate cancers are here identified as differences between luminal and basal cells in both normal and cancer samples. We also identified changes unique to each of the two cancer subpopulations. Those specific to cancer luminal cells were associated with regulation of metabolic processes, cell proliferation and epithelial development. Within the prostate cancer TCGA dataset, these changes were able to distinguish not only cancers from normal samples, but also organ-confined cancers from those with extraprostatic extensions. Using changes present in both basal and luminal cancer cells, we derived a new 17-CpG prostate cancer signature with high predictive power in the TCGA dataset.ConclusionsThis study demonstrates the importance of comparing phenotypically matched prostate cell populations from normal and cancer tissues to unmask biologically and clinically relevant DNA methylation changes.
Highlights
Human prostate cancers display numerous DNA methylation changes compared to normal tissue samples
EpCAM+/CD49f+/CD24− cells expressed higher levels of molecular markers associated with basal cells and lower levels of luminal markers compared to EpCAM+/CD49f−/CD24+ cells from the same biopsy, both at the mRNA and protein level (Supplementary Fig. 1A, B)
We named the paired subsets as follows: Cancer Luminal (CL) EpCAM+/CD49f−/CD24+ cells purified from tumour-directed biopsies; Cancer Basal (CB) EpCAM+/CD49f+/CD24− cells purified from tumour-directed biopsies; Normal Luminal (NL) EpCAM+/CD49f−/CD24+ cells from contralateral biopsies; Normal Basal (NB) EpCAM+/CD49f+/CD24− cells purified from contralateral biopsies
Summary
Treatment-naïve prostate cancer (PCa) is characterised by an abnormal accumulation of proliferative cells with a molecular phenotype similar to the luminal cells present in the normal prostate.[1,2] PCa samples contain a small population of tumour cells with basal features. Our results show that many DNA methylation changes frequently seen in PCa are characteristic differences between luminal and basal cells from both normal and cancer samples. From these datasets, we were able to identify two sets of tumour-specific changes of potential clinical interest. The optimal model was tested on the remaining 30% of samples and receiver operating characteristic curve and area under the curve (AUC) calculated using the ROCR package
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