Exploring the DNA Methylome in mCRPC Through NGS of Plasma DNA Specimens – Cancer Therapy Advisor

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

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

Because DNA methylation/demethylation can affect gene expression, anunderstanding of the tumor methylome can provide information on gene regulationin different cancers.

In this study, circulating cell-free DNA collected from plasmaspecimens of 25 patients with mCRPC who had undergone treatment with either ofthe antiandrogen therapies, abiraterone, or enzalutamide within the prior 30days 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 pretreatedwith sodium bisulfite, a targeted enrichment approach based on previousknowledge of regions of DNA known to be associated with cancer. Plasmaspecimens were also collected from 2 healthy male volunteers.

The limited number of common genomic alterations in the plasmaspecimens of patients with cancer, the potential presence of clonalhematopoiesis in older patients, and the large number of plasma DNA fractionsfrom both normal DNA and tumor DNA (ie, either specific to the cancer or theprostate epithelium) were part of the rationale for evaluating both the genomeand methylome of plasma DNA specimens.

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

A key finding from this study was that theplasma methylome of patients with mCRPC was globally more hypomethylatedcompared with plasma specimens from healthy volunteers. Specifically, the studyauthors concluded that the main contributor to methylationvariance was strongly correlated with genomically determined tumor fraction, and that plasmamethylome analysis can accurately quantitate tumor fraction.

Among the tumor-specific DNA methylationsignatures observed in this study was an enrichment in hypomethylated androgenreceptor binding sequences associated with a gain in androgen receptor copynumber 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

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Exploring the DNA Methylome in mCRPC Through NGS of Plasma DNA Specimens - Cancer Therapy Advisor