Currently in the diagnosis of prostate cancer, in patients with Gleason score 7 cancer, no prognostic markers are able to distinguish between those whose cancer will and will not recur. Unfortunately, this group represents the largest number of patients at presentation. The consequences of ineffective risk assessment are under-diagnosis (increasing the number of deaths from cancer) or over-diagnosis (increasing the treatment-associated morbidity and life-altering side effects). Thus, new markers that can improve predictions of disease progression and treatment planning of patients with prostate cancer are needed.
Here we show that PMS2, a MMR protein that is elevated in prostate cancer, predicts biochemical recurrence in a population of patients containing Gleason score 7 prostate cancer treated by prostatectomy. The levels of PMS2 were consistently higher in recurrent individuals (). The levels of PMS2 in both cancer and the cancer-surrounding benign epithelium were able to stratify patients based on recurrence (), while PMS2 levels in the benign epithelium surrounding the cancer were actually predictive of disease recurrence (). When used in combination, PMS2 was able to improve the prognostic sensitivity of total percent Gleason 4/5 by 12% (). The presence of PMS2 in benign tissue is reminiscent of previous reports on risk markers that were found to be present in cancer-associated, benign tissue (28
) and suggests that PMS2 elevation is an early event in prostate tumorigenesis.
The search for molecular prognostic indicators has produced a number of markers that can be detected immunohistochemically and that correlate with prostate cancer progression. Well-characterizedmarkers include Bcl-2 family proteins (30
), CDK1/p34 (35
), insulin-like growth factor binding proteins (41
), Ki67 (30
) and PTEN (48
). Many more potential biomarkers are the subject of further investigation and verification (50
). Like PMS2, many of these markers are detectable in tissue samples and correlate with patient outcome. PMS2 is unique, however, in that its quantitation in histologically benign epithelium adjacent to the tumor is informative for biochemical relapse. Also, while the well-characterized markers mentioned above are primarily indicators and effectors of cellular proliferation or apoptotic activation, PMS2 elevation is associated with genomic instability and mutagenesis.
Elevation of PMS2 has previously been shown to have biological consequences including: increased mutation frequency (14
), increased resistance to methylation-induced apoptosis (14
), reduced mismatch repair (52
) and microsatellite instability in tumors (15
). PMS2 elevation even in early, pre-neoplastic PIN lesions (15
) indicates that it may be an early event in tumorigenesis. The discovery that PMS2 levels in cancer-surrounding benign epithelium are predictive of biochemical recurrence suggests that PMS2 may be a consequence of early changes in the tumor microenvironment that contribute to aggressive tumor formation. At this point, the exact role of PMS2 elevation in tumorigenesis is still speculative but may involve aberrant and improper binding to inactivate the MMR system. This mechanism would be consistent with the biological consequences already associated with PMS2 elevation.
As this study was retrospective and would be defined as a Phase 2 biomarker study(53
), further studies are required to 1.) validate these findings in an independent patient population, 2.) to investigate the effect of treatment (e.g. radiation, adjunct chemotherapy) and, 3.) to determine a standardized scale of PMS2 quantitation. Overall, this study confirms previous findings of a MMR protein, PMS2, being elevated in a significant proportion of prostate cancer (15
) and demonstrates that PMS2, is a novel prognostic indicator for biochemical recurrence after surgery.