Abstract
Background:The early detection of prostate cancer has resulted in an increase in the number of patients with localized prostate cancer and has paralleled the reported reduction in prostate cancer mortality. The increased rate of detection of patients with localized prostate cancer may also increase the risk of potentially morbid therapy in a patient with indolent cancer. Defining the biomarker correlates of prostate cancer virulence will facilitate the appropriate application and development of therapy for patients with early disease.Methods:A 255 core prostate cancer tissue microarray (TMA) from 47 prostatectomy specimens with organ confined tumor was constructed. Prostate cancer foci of transition and peripheral zone origin were represented on the TMA. Further, replicate cores of the two Gleason grades comprising the Gleason score, representative of Gleason scores 5-9, were arrayed from each prostatectomy specimen. Standard immunohistochemical techniques were used to assess expression of nine, cell death and cell cycle regulatory proteins implicated in the pathogenesis of prostate cancer (bax, bcl-2, bcl-xL, bin1, CD95, mdm2, p21, p53, and NFkB).Results:The Spearman correlation coefficient revealed a strong correlation of bax, bin1, FAS, p65 and p21 expression with Gleason grade. Spearman correlation coefficients showed that expression of, bax and bin1, bax and MDM2, Bax and p21, and bax and p65 NFkB was highly associated. Other significant associations were identified between bin1 and p21, bin1 and MDM2, bin1 and p65 NFkB and between p21 and p65 NFκB. A model for predicting the biological potential of Gleason score 7 prostate cancer using multivariable logistic regression methods was developed. The findings also indicate that the profile of specific markers for Gleason grade 3 prostate cancer correlates with the overall context of the Gleason score.Conclusion:These data support the view that important molecular differences exist among and between the Gleason scores. Furthermore, there is significant molecular heterogeneity among prostatectomy specimens containing Gleason grade 3 cancer. This observation may have broader implications regarding the determination of risk among patients with prostate cancer that is currently considered to be of either good prognosis or unclear prognosis, i.e. Gleason score 7 tumors.
Highlights
The early detection of prostate cancer has resulted in an increase in the number of patients with localized prostate cancer and has paralleled the reported reduction in prostate cancer mortality
A model for predicting the biologic potential of Gleason score 7 prostate cancer using multivariable logistic regression methods was developed. These findings indicate that the profile of specific markers for Gleason grade 3, a critical component of Gleason score 7, prostate cancer correlates with the overall context of the Gleason score
Construction of Prostate Tissue Microarray A 255 core tissue microarray (TMA) was constructed from formalin-fixed and paraffin-embedded prostatectomy specimens obtained from patients with prostate cancer as described in the methods
Summary
The early detection of prostate cancer has resulted in an increase in the number of patients with localized prostate cancer and has paralleled the reported reduction in prostate cancer mortality. The increased rate of detection of patients with localized prostate cancer may increase the risk of potentially morbid therapy in a patient with indolent cancer. The prediction of outcome in prostate cancer would immediately benefit a portion of patients diagnosed with early stage prostate cancer detected because of the widespread application of PSA screening. The dilemma of most patients with prostate cancer is that they are increasingly comprised of low volume Gleason score 7 tumors detected by routine screening exposing some patients to the risk of unnecessary intervention. This heterogeneity has made it difficult to perform efficient clinical investigation in these patients
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