Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status

The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.