Gene Pair Distinguishes Forms of Prostate Cancer

Cancer researchers have identified a biomarker comprising a pair of genes that distinguishes between indolent and aggressive prostate cancers.

Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated deaths. However, current clinical parameters cannot distinguish between patients with indolent disease from those with aggressive prostate cancer.

Recently this situation has begun to change due, in part, to the discovery by researchers at the Dana-Farber Cancer Institute (Boston, MA, USA) that elevated expression of two genes, TOP2A (encoding the enzyme DNA topoisomerase 2-alpha) and EZH2 (encoding the enzyme Enhancer of zeste homolog 2), was associated with early recurrence of prostate cancer and metastatic spread.

The TOP2A gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA, which allows the strands to pass through one another, thus altering the topology of DNA.

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Mutation or over-expression of EZH2 has been linked to many forms of cancer. EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth.

The investigators interrogated a total of seven primary prostate cancer cohorts, two metastatic castration resistant prostate cancer datasets, and one control cohort to assess the impact of TOP2A and EZH2 expression on the prostate cancer cellular program and patient outcomes. They also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of 89 primary prostate cancer patients with known outcomes. In addition, they explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived mouse cell lines.

Results of genome-wide analysis of independent primary and metastatic prostate cancer datasets demonstrated that concurrently elevated TOP2A and EZH2 mRNA and protein were indicative for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells acted as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.

"Other biomarkers and genetic signatures are being used in an effort to predict the aggressiveness of an individual patient’s prostate cancer," said senior author Dr. Leigh Ellis, an investigator in the department of oncologic pathology at the Dana- Farber Cancer Institute, "but the current information does not make it possible for their gene signature to be an actual target for precision medicine targeted therapy."

The prostate cancer paper was published in the September 12, 2017, online edition of the journal Clinical Cancer Research.

Related Links:
Dana-Farber Cancer Institute