Just a follow-up to my previous post, Gene Fusion Prostate Cancer--USCAP 2010, Dr. Rubin's group published their findings of the prevalence of TMPRSS2, SLC45A3, and NDRG1 in a large prostatectomy cohort in the April 2010 Modern Pathology (abstract).
More from the Special Course, "Basic Principles and Practice of Molecular Pathology in Cancer," that I attended at the USCAP 2010 meeting.
Dr. Mark Rubin discussed testing for ETS rearranged prostate cancer during the course and here's my highpoints:
There is a critical need for a specific biomarker for clinically significant prostate cancer (PCa) because of the problems with the serum PSA test and the clinical variability of PCa itself.
Recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 with ERG and ETV1 (members of the ETS transcription factor family) were discovered about 5 years by a bioinformatics study of PCa.
Gene rearrangement of the androgen-responsive elements that normally restrict TMPRSS2 expression drives aberrant overexpression of 5' truncated ETS oncogenes.
Over 30 studies have shown ETS gene fusions in about 50% of PSA-detected PCa and 15%-35% of unscreened PCa--the reasons for this discrepancy are not clear. Gene fusion detected by FISH and overexpression of ETS gene fusion transcripts is essentially 100% specific for PCa.
SLC45A3 and NDRG1 (N-myc Downstream Regulated Gene 1) are alternative 5' fusion partners with ERG.
Dr. Rubin's group presented an abstract of their study of 540 PCa cases with ERG rearrangements to identify the frequency of the three 5' fusion partners and found that TMPRSS2 was the only fusion partner in 78% of cases, SLC45A3 the only partner in 6% of cases, and concurrent TMPRSS2 and SLC45A3 in 11% of cases. One case of NDRG1 rearrangement was found and no TMPRSS2 or SLC45A3 rearrangement was found in 5% of cases.
Assessing ETV1, ETV4 and ETV5 fusions is best done by FISH.
Multiple lines of evidence suggest that ERG rearranged PCa represents a distinct clinical subclass of PCa that if untreated, has an unfavorable course compared to non-ERG-rearranged PCa and appears to also selectively respond to abiraterone acetate, a CYP17 inhibitor.
However, some have pointed out that the frequency of ETS rearranged PCa cases (40%-60%) is inconsistent with the observed frequency of clinically aggressive PCa.
Recent animal models suggest that ETS overexpression by itself is insufficient to drive disease progression and that PTEN loss or alteration of the PI3K/AKT/PTEN pathway is also required. Keep an eye on developments in this area.
Gene fusion (TMPRSS2-ERG) PCa may have more immediate implications as urine-based assays to detect PCa in men at risk for PCa and tissue-based FISH assays to identify ERG rearranged PCa for prognosis come online.