Topoisomerase II alpha Protein Expression Is Predictive of Outcome in Gleason Score ≥ 7 Prostate Cancer Patients Treated Surgically and Is Dependent on ERG Status
CM Ida, JC Cheville, RJ Karnes, JM Munz, G Vasmatzis. Mayo Clinic, Rochester, MN
Background: Recently, a prognostic model for high Gleason Score (GS) prostate cancer (GS ≥7) consisting of gene expression of TOP2A and CDH10, TMPRSS2-ERG fusion and DNA ploidy was described. Topoisomerase II alpha gene (TOP2A), which encodes an enzyme involved in DNA replication, was the strongest predictor of outcome. TMPRSS2-ERG fusion is a frequent recurrent abnormality believed to represent an early event in prostate carcinogenesis. It results in ERG gene overexpression and its association to tumor aggressiveness is controversial. We evaluated the prognostic value of TOPO2A protein expression in comparison to TOP2A mRNA expression in GS >7 prostate cancer in the context of ERG status defined by high (ERG+) or low (ERG-) mRNA expression.
Design: GS ≥7 patients that developed systemic progression or died of prostate cancer within 5 years following surgery (n=140, cases) and patients free of disease within at least 7 years of follow-up (n=117, controls) were identified. A computerized score combining GS, margin status and preoperative serum PSA, was used to match cases and controls. ERG and TOP2A mRNA levels were measured by qRT-PCR. TOP2A protein expression was assessed by immunohistochemical (IHC) analysis and quantified using IHC Score Software (Bacus Laboratories, Inc.) to obtain TOP2A labeling indices (LIs).
Results: TOP2A LIs mean±SD for cases and controls were 3.45±5.18 (range, 0.02-30.74) and 0.92±1.34 (range, 0.01-7.09), respectively (pீ0.001). In addition, TOP2A protein expression was a superior prognostic indicator than TOP2A gene expression (AUC 0.75 for IHC analysis vs. 0.70 for qRT-PCR). Notably, the prognostic ability of TOP2A IHC was dependent upon the ERG status. In ERG- prostate cancer, TOP2A IHC was a stronger predictor of outcome (AUC 0.81 for ERG- vs. AUC 0.67 for ERG+).
Conclusions: TOP2A IHC protein expression by immunohistochemistry was predictive of systemic progression and death in patients with GS ≥7 prostate cancer treated surgically, especially in prostate cancer without ERG overexpression. Therefore, TOP2A protein expression is a potential prognostic predictor to individualize postoperative therapy based on risk of systemic progression.
Category: Pan-genomic/Pan-proteomic Approaches to Diseases
Monday, March 22, 2010 1:00 PM
Poster Session II # 233, Monday Afternoon