Fresh Look at Gene Fusion Yields Clues in Low-Risk Prostate Cancer

Gina Battaglia, PhD
Published: Wednesday, Jan 10, 2018
John C. Cheville, MD
John C. Cheville, MD
Although gene fusions between the TMPRSS2 gene and ETS family of transcription factors (most commonly the ERG gene) in prostate cancer have been recognized for more than a decade, the clinical relevance of this fusion event continues to be debated among experts. However, the findings of a recent study suggests that the mechanism through which this fusion occurs may be more important than the presence of the fusion for identifying low-risk prostate cancers, since retention of the interstitial genes between the TMPRSS2 and ERG genes post fusion occurred more frequently in prostate cancers classified as very low or low risk.1

If these larger trials confirm these findings, testing for the retention or deletion of this segment could help predict which patients would benefit from active surveillance, according to senior author John C. Cheville, MD, consultant in the Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, and professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota.

Cheville also stated that development of efficient, clinically relevant assays will be important for testing for this fusion event in large groups of patients first in the clinical trial setting and perhaps later in the clinic. These assays may also help determine the dynamic behavior of this fusion event in the primary and metastatic settings. The finding comes amid ongoing interest in developing molecular assays that would help stratify risk for men with newly diagnosed prostate cancer considering active surveillance.

Although tissue-based molecular assays have not been incorporated into National Comprehensive Cancer Network guidelines, several tests are likely to be covered by CMS.2 Additionally, the Michigan Prostate Score is being developed as an early detection test for prostate cancer combining serum prostate-specific antigen with urinary PCA3 and TMPRSS2-ERG expression.3

Knowledge About Fusion Event

Fusion between the TMPRSS2 gene and the ETS transcription family is thought to be an early event that occurs in approximately half of all prostate cancers, although the mechanisms for this fusion are not completely clear. ETS family members are involved in the regulation of cell growth, proliferation, differentiation, and apoptosis via activation or repression of its target genes. In prostate cancer, the positioning of androgen-responsive promotors in frame is thought to initiate overexpression of the members of the ETS family. For example, the androgen-responsive gene TMPRSS2 is fused near its first exon with its promoter in frame with the 5’ exons of the ERG gene, which retains the characteristic functional domains of the ETS family.

The high prevalence of the androgen-regulated overexpression of ETS family fusions suggests their key role in the development of prostate cancer. However, results from in vivo mouse studies4 showed that overexpression of ERG led to development of prostatic intraepithelial neoplasia but not cancer, suggesting that although the fusion event may contribute to initiation of prostate cancer, other subsequent driver mutations (eg, PTEN loss) may be necessary to drive progression to cancer.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Current Perspectives on Preventing and Managing Tumor Lysis SyndromeJun 30, 20191.0
Community Practice Connections™: 2nd Annual International Congress on Oncology Pathology™Aug 31, 20191.5
Publication Bottom Border
Border Publication