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Metastatic Prostate Cancer Methylation Analysis Reveals Subtype, Ties to Driver Genes

NEW YORK – New research from a team led by scientists at the University of California, San Francisco points to a previously unappreciated subtype of metastatic castration-resistant prostate cancer (mCRPC) with enhanced DNA methylation, which might open new avenues for treatment with methylation inhibitors.

"Although genomic and transcriptomic subtypes of [prostate cancer] have been described, we have identified a new epigenetic [CpG methylator phenotype] subtype of mCRPC that is characterized by hypermethylation both within and outside CpG islands, shores, and shelves," co-senior and corresponding author Felix Feng, a professor of radiation oncology, urology, and medicine at UCSF, and his colleagues wrote. They noted that the results also point to the "importance of cancer-associated hypomethylation in overexpression of oncogenic drivers in mCRPC."

Using a combination of bisulfite sequencing-based methylation profiling, whole-genome sequencing, and RNA sequencing, the researchers profiled metastatic samples from 100 mCRPC cases, identifying a hypermethylation subtype marked by TET2, DNMT3B, IDH1, and BRAF somatic mutations in more than 20 percent of the tumors tested.

With the integrated data, the team also uncovered apparent ties between the expression of driver genes such as MYC or the androgen receptor gene AR and methylation patterns at sequences falling between genes. The findings, appearing in Nature Genetics on Monday, also highlighted somatic mutation hotspots and apparent regulatory sequences that appeared particularly prone to lower-than-usual DNA methylation in the mCRPC tumors.

"These data identified a novel epigenetic subtype of mCRPC, new intergenic regulatory regions of AR, and the interplay between somatic and epigenetic alterations in the regulation of AR, ERG, MYC, and other important [prostate cancer] drivers," the authors reported. "We also demonstrated global methylome changes that distinguish benign prostate, primary [prostate cancer], and mCRPC."

For their analyses, the researchers performed whole-genome bisulfite sequencing on fresh frozen biopsy samples from 100 mCRPC patients and 10 matched normal samples collected prospectively at several sites. They also generated whole-genome sequence and RNA-seq data on matched tumor and normal samples.

Despite efforts to characterize methylation in prostate cancers in the past, the authors noted, whole-genome bisulfite sequencing "has rarely been integrated with other genome-wide sequencing approaches such as whole-genome sequencing and whole-transcriptome RNA-seq."

From these sequences — along with available methylation, chromatin interaction, and other data reported for metastatic prostate cancer, primary prostate cancer, and benign prostate samples in past studies — the team tracked down tens of thousands of hypomethylated regions per mCRPC tumor tested. Those regions of reduced DNA methylation appeared to be a bit more common in tumors with frequent copy number changes, they noted, and tended to turn up at sites corresponding with apparent regulatory regions.

But the researchers also saw 22 mCRPC tumors with so-called CpG methylation (CMP) phenotypes that had enhanced DNA methylation, often coinciding with mutually excusive somatic mutations in TET2, IDH1, BRAF, or DNMT3B. Those alterations hinted that at least some mCRPC tumors may be amenable to methylation inhibitors proposed in other cancer types, they noted, though more work is needed to untangle this CMP phenotype in prostate cancer.

"There are potential therapeutic implications of the mCRPC CMP subtype, as methylation inhibitors such as 5-azacytidine and 5-aza-2-deoxycitidine are FDA-approved anti-neoplastic drugs," the authors wrote, noting that "[i]n vitro data, as well as clinical data, suggest that hypermethylated tumors may preferentially benefit from these treatments."

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