Differential expression of the mismatch repair gene hMSH2 in malignant prostate tissue is associated with cancer recurrence

Abstract

BACKGROUNDMismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high‐grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported.METHODSImmunohistochemical analysis of benign and malignant prostate tissue from 101 patients was performed using a monoclonal antibody specific for the hMSH2 protein. Expression was correlated with MSI using dinucleotide repeat markers and laser‐captured microdissected DNA from normal and tumor cells. hMSH2 protein expression and MSI were assessed with respect to pathologic stage, Gleason score, and time to detectable serum prostate specific antigen (PSA) after prostatectomy in patients with clinically localized prostate carcinoma.RESULTSIn normal glands, hMSH2 staining was minimal to low and confined to the basal cell layer. In 32% of benign prostatic hyperplasia cases, hMSH2 staining was increased in the basal and luminal cell layers whereas 71% of cancer specimens had uniform moderate to high staining. Microsatellite instability was detected in 60% of absent to low staining and 26% of moderate to high staining prostate carcinoma specimens. Differential staining in benign versus malignant prostate tissues was statistically significant (P < 0.001) as was the correlation between absent to low hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA recurrence after radical prostatectomy correlated with absent to low hMSH2 staining in malignant prostate tissue but was only marginally significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall time to PSA recurrence).CONCLUSIONSThe results of the current study demonstrate differential hMSH2 expression in benign and malignant prostate tissue. Moreover, hMSH2 expression is altered in a subset of clinically localized prostate carcinoma specimens independent of pathologic stage and Gleason pattern. A statistically significant correlation between hMSH2 immunohistochemical staining intensity and MSI also was identified in prostate carcinoma specimens. Furthermore, the time to cancer recurrence as determined by detectable serum PSA after prostatectomy was associated with hMSH2 staining intensity. Taken together, our results suggest that hMSH2 gene expression in prostate carcinoma may be a useful prognostic marker for outcome in men with clinically organ confined prostate carcinoma. Cancer 2002;94:690–9. © 2002 American Cancer Society.DOI 10.1002/cncr.10247

Mismatch repair expression in testicular cancer predicts recurrence and survival

“…All immunostainings were performed in duplicate as previously described in detail. 13,14 A grading system for MMR expression based on degree of immunostaining relative to fibroblasts, smooth muscle and lymphocytes has been described in detail. 13 Absent, minimal or low staining was graded 0-2; moderate and high staining 3-4.…”

“…13,14 A grading system for MMR expression based on degree of immunostaining relative to fibroblasts, smooth muscle and lymphocytes has been described in detail. 13 Absent, minimal or low staining was graded 0-2; moderate and high staining 3-4. For analytical purposes, absent, minimal or low staining were considered as 1 group, while moderate and high staining were considered as another.…”

“…[5][6][7] Sporadic inactivation of MMR genes and MSI is also found in a variety of tumors, including genitourinary malignancies arising from the prostate, kidney, bladder and testicles. [12][13][14][15][16][17][18][19] We previously investigated the potential role of MMR gene expression in GCT and found a subset of these tumors that exhibit differential expression of the MMR gene MSH2. 20,21 Furthermore, these tumors exhibit MSI and appear to have a different prognosis relative to GCT with an intact MMR system.…”

Molecular biology of prostate cancer

“…MSI was detected in 60% of specimens with absent to low hMSH2-staining and in 26% of moderate to high hMSH2-staining PC specimens. 275 The relative expression levels of hMSH2 and hMLH1 were significantly lower in cases than in controls (Po0.05 for both genes). When compared with controls, low expression levels of hMLH1 were associated with significantly increased risk of PC after adjustment for age, ethnicity, smoking status and family history of PC.…”

“…274 Thus, MMR deficiency particularly causes instability at microsatellites and increased mutation rates in general. 275 The MMR genes (hMLH1, hPMS1, hPMS2, hMSH2, hMSH3, hMSH6) generate mRNA transcripts in all PC cell lines. 276 MSI has been described in high-grade and lymph node positive PC specimens.…”