Results of a study that used next-generation sequencing (NGS) to evaluate both the genome and methylome of circulating plasma DNA from patients with metastatic castration-resistant prostate cancer (mCRPC) revealed different subtypes of the disease associated with different clinical courses. These findings were published in the Journal of Clinical Investigation.

Epigenetic changes to DNA, such as methylation of cytosine residues that are sequentially followed by guanine (ie, CpG dinucelotides) can be detected through sequencing of DNA treated with sodium bisulfite, which reacts with unmethylated (but not methylated) cytosine.

Because DNA methylation/demethylation can affect gene expression, an understanding of the tumor methylome can provide information on gene regulation in different cancers.

In this study, circulating cell-free DNA collected from plasma specimens of 25 patients with mCRPC who had undergone treatment with either of the antiandrogen therapies, abiraterone, or enzalutamide within the prior 30 days was treated with and without sodium bisulfite.

Subsequent NGS DNA analysis was performed using high-coverage targeted- or whole-exome sequencing of untreated DNA or, in the case of DNA pretreated with sodium bisulfite, a targeted enrichment approach based on previous knowledge of regions of DNA known to be associated with cancer. Plasma specimens were also collected from 2 healthy male volunteers.

The limited number of common genomic alterations in the plasma specimens of patients with cancer, the potential presence of clonal hematopoiesis in older patients, and the large number of plasma DNA fractions from both normal DNA and tumor DNA (ie, either specific to the cancer or the prostate epithelium) were part of the rationale for evaluating both the genome and methylome of plasma DNA specimens.

The primary aim of this study was to identify specific DNA methylation signatures associated with mCRPC since results of previous studies showed that changes in DNA methylation in this setting were associated with a more aggressive clinical course. 

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A key finding from this study was that the plasma methylome of patients with mCRPC was globally more hypomethylated compared with plasma specimens from healthy volunteers. Specifically, the study authors concluded that “the main contributor to methylation variance was strongly correlated with genomically determined tumor fraction,” and that “plasma methylome analysis can accurately quantitate tumor fraction.” 

Among the tumor-specific DNA methylation signatures observed in this study was an enrichment in hypomethylated androgen receptor binding sequences associated with a gain in androgen receptor copy number in patients with a more aggressive phenotype.

In their concluding remarks, the study authors noted that “studies in more prostate cancer patients across the disease spectrum and healthy volunteers are required to validate our methylation subtyping signatures and confirm response prediction.”

Reference

Wu A, Cremaschi P, Wetterskog D, et al. Genome-wide plasma DNA methylation features of metastatic prostate cancer [published online March 9, 2020]. J Clin Invest. doi: 10.1172/JCI130887