Mismatch repair expression in testicular cancer predicts recurrence and survival

Abstract

We investigated mismatch repair (MMR) gene expression in testicular cancer as a molecular marker for clinical outcome (recurrence, response to chemotherapy and death) using protein expression and specific genetic alterations associated with the presence or absence of MMR activity. One hundred sixty-two cases of paraffin-embedded testis cancer specimens were subjected to immunohistochemical analysis using monoclonal antibody for MLH1 and MSH2 MMR proteins and genetic analysis using specific polymorphic markers. The degree of MMR immunoreactivity and genetic instability in the form of loss of heterozygosity (LOH) and/ or microsatellite instability (MSI) were determined by comparing matched normal and tumor tissue. The degree of immunohistochemical staining for MMR expression was associated with a shorter time to tumor recurrence, resistance to chemotherapy and death. Furthermore, clinical relapse and cancer specific death was also associated with tumors exhibiting a high degree of MSI, p 5 0.01 and 0.04, respectively. In contrast, LOH was not associated with recurrence, resistance to chemotherapy or death. Therefore, MMR expression defines testis cancers with distinct molecular properties and clinical behavior, such that tumors with decreased MMR immunostaining and/or increased frequency of MSI have a shorter time to recurrence and death despite chemotherapy. ' 2007 Wiley-Liss, Inc.

Mismatch Repair Protein Deficiency Compromises Cisplatin-induced Apoptotic Signaling

“…Low levels of MMR protein post-chemotherapy seem to be predictive of lower overall survival in a certain subset of tumors (esophageal cancer), but not others (ovarian and non-small cell lung cancer) (19 -21). Two recent studies examining MMR protein levels and microsatellite instability in germ cell tumors from patients receiving platinum-based chemotherapy have suggested a prognostic value for pre-chemotherapy MMR protein status in these tumors (22,23). This potential clinical relevance underscores the need for a greater understanding of MMR proteindependent mechanisms of CDDP-induced cell death.…”

The Association of CCND1 Overexpression and Cisplatin Resistance in Testicular Germ Cell Tumors and Other Cancers

“…4,5,8,12 The association between microsatellite instability/mismatch repair and resistance has been extensively investigated. Although the results from different studies were controversial, [12][13][14][15][16] a recent study of a large series of resistant TGCT samples generally confirmed the involvement of microsatellite instability/mismatch repair in cisplatin resistance, and also revealed the association between BRAF mutation and cisplatin resistance. 17 Seladin-1, a multifunctional protein, has also recently been identified as a putative player in cisplatin sensitivity of TGCTs.…”

Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

“…One hundred unselected cases from study by Mayer et al were used later as a control cohort in the study by Honecker et al (2009) (Table 2). Velasco et al (2008) assessed the MMR enzyme expression and MSI in 162 TGCT patients, with a majority having seminomas. The authors found a negative correlation between MSI and survival.…”

“…In TGCT, the roles of MSI and BRAF mutations are poorly characterized and controversial results have been reported (Huddart et al, 1995;Mayer et al, 2002;Velasco et al, 2004Velasco et al, , 2008Sommerer et al, 2005;Honecker et al, 2009;MasqueSoler et al, 2011). Therefore, in the present study, we evaluated the presence and clinical impact of MSI and BRAF mutations in a large series of TGCTs.…”