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Prostate Cancer Metastasis Linked to Development-Related Epigenetic Shift

NEW YORK – Prostate cancer metastases may involve DNA methylation shifts that push tumor cells toward features that resemble those found during human development, according to a new study by a Dana-Farber Cancer Institute- and Netherlands Cancer Institute-led team.

"The reactivation of these programs is presumably important for the spread of the disease, and if we could understand it better, and potentially block or inhibit the process, it may help us to suppress metastatic prostate disease," co-senior and co-corresponding author Matthew Freedman, a medical oncologist affiliated with Dana-Farber and the Broad Institute, said in a statement.

Using whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, ATAC-seq chromatin accessibility analyses, and other approaches, Freedman and colleagues generated epigenetic profiles spanning up to 113 primary prostate tumors, 93 histologically normal prostate samples, and dozens of patient-derived xenograft or fresh-frozen samples generated from androgen receptor-positive, metastatic castration-resistant prostate cancer cases — datasets they analyzed alongside epigenetic data from fetal samples and cell lines representing early stages of prostate development.

"Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression," the authors wrote, noting that "comprehensive results of our epigenomic analysis provide a foundation for further investigation into the mechanisms underlying tumorigenesis and cancer progression."

The team's findings, appearing in Nature Genetics on Monday, suggested that the androgen receptor (AR) reprogramming that occurs as prostate cancers slide into metastasis spin out of regulatory element activity related to early stages of prostate development and enhancers that impact transcription factors from normal prostate samples.

"[W]e demonstrate that reprogrammed AR sites do not arise de novo," the authors reported, explaining that "the [prostate cancer] cell — specifically in the transition to metastatic disease —reactivates latent regulatory elements active during fetal prostate organogenesis."

Although past studies have shown that binding sites for the androgen receptor transcription factor are shuffled in the process of prostate cancer malignancy, the team noted, the new analysis provides a broader look at epigenetic dynamics in normal prostate tissue, primary tumors, and more advanced forms of disease.

By combining DNA methylation, histone modification, and other epigenetic cues with somatic mutation details from the primary and metastatic prostate cancer cases, the researchers were also able to track down chromatin states that often corresponded with specific alterations while highlighting related prostate-specific regulatory features that appeared to track with germline risk variants for prostate cancer or with somatic changes found in the tumors.

In a related study published in Nature Genetics last week, researchers from the University of California at San Francisco and elsewhere described an epigenomics-based subtype of castration-resistant, metastatic prostate cancer, along with other methylation features that coincide with specific genetic or genomic alterations.