The Molecular Pathology Of Low-Risk Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 12 Jun 2008 - 11:00 PDT

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UroToday.com - In the online version of the World Journal of Urology, Drs. Samaratunga and Epstein present a Topic Paper on molecular pathologic characteristics that may be predictive for indolent, low-risk prostate cancer (CaP). Low risk CaP is defined as clinical stage T1c or T2a, Gleason score <6, and PSA<10ng/ml.

A variety of chromosomal aberrations are associated with CaP. In particular, rearrangements in 21q are found in over 50% of CaPs. Loss of 8p is present in high-grade PIN and thus may reflect an early alteration. In contrast, gains of 7pq and /or 8p are associated with progression and may discriminate those at risk for more aggressive CaP. The gene fusion between the androgen-regulated TMPRSS2 gene to the ETS family oncogenic transcription factors is a common event and can be identified by FISH or RT-PCR. The TMPRSS2-ERG fusion is identified in 50% of surgical specimens but only 15% of early CaP patients on active surveillance. However, it is not noted in BPH or inflammatory conditions but is found in 20% of high-grade PIN.

Tumor proliferation can be assessed by immunohistochemical staining for Ki-67. It is linked to Gleason score, and as such may not be useful in low grade lesions. Tumor suppressor genes such as p53 have conflicting data. The mutation and nuclear accumulation of the p53 protein in most studies is correlated with advanced CaP. P27, an inductor of cell cycle arrest is a significant predictor of recurrence free survival when expressed in low amounts. Overexpression of the c-MYC oncogene is negatively correlated with pathologic stage and Gleason score and may have utility is defining low risk CaP. On the other hand, the adhesion molecule E-cadherin has low expression in the metastatic setting, but levels of expression are variable even within one specimen.

Signaling molecules, apoptosis regulators, cytokines such as IL-6 and its receptor are either not correlated with low risk CaP or require further study. Thus, while molecular evaluation of prostate biopsy tissue is possible, only TMPRSS2-ETS rearrangements at this time hold much promise. Serum markers are another potential biomarker, but further investigation is clearly needed. This leaves Gleason score and PSA doubling time as the clinical variables to monitor active surveillance at present.

Samaratunga H, Epstein JI
World J Urol. 2008 Apr 12 (Epub ahead of print)
doi:10.1007/s00345-008-0260-5

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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