Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer

• Published in: The Prostate Vol. 67; no. 2; pp. 214 - 225
• Main Authors: Norris, Alixanna M., Woodruff, R.D., D'Agostino Jr, Ralph B., Clodfelter, Jill E., Scarpinato, Karin Drotschmann
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-02-2007; Wiley-Liss
• Subjects: Adaptor Proteins, Signal Transducing; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; DNA Mismatch Repair; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; human prostate cancer; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Male genital diseases; Medical sciences; microsatellite instability; Microsatellite Repeats - genetics; Mismatch Repair Endonuclease PMS2; mismatch repair protein; MutL Protein Homolog 1; MutS Homolog 2 Protein - genetics; MutS Homolog 2 Protein - metabolism; Nephrology. Urinary tract diseases; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PMS2 elevation; Prognosis; prognostic marker; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Incompatibility; Andrology; microsatellite instability; Nephrology; Urinary system disease; Prognosis; Prostate disease; Gynecology; Biological marker; Biological indicator; mismatch repair protein; Malignant tumor; Protein; Repair gene; prognostic marker; Microsatellite DNA; Instability; Repair; Male genital diseases; Prostate cancer; human prostate cancer; PMS2 elevation
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20522

Background
Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis. This study determined alterations in key MMR protein levels in prostate cancer with the goal to identify prognostic markers.
Methods
Prostatectomy samples were immunohistochemically stained and the relative presence or absence of key proteins MSH2, MLH1, and PMS2 determined. Cancer tissue of distinct grades was compared with the normal surrounding tissue. Microsatellite instability (MSI) in altered tissues was determined according to NCI guidelines.
Results
In contrast to reports that associate a lack of individual MMR proteins with tumorigenesis, a significant increase in PMS2 levels was identified in PIN lesions and prostate cancer tissue. This elevation in PMS2 was independent of changes in levels in its heterodimeric partner, MLH1. Prostate tumors with elevated levels of PMS2 were genetically unstable, which was corrected by MLH1 co‐elevation.
Conclusions
This is the first documentation of detrimental consequences associated with the increase in a MMR protein in human cancer. This study recognizes PMS2 elevation as a prognostic marker in pre‐neoplastic and prostate cancer lesions. This result has significant implications for future diagnostic and treatment measures. Prostate © 2006 Wiley‐Liss, Inc.