ORIGINAL ARTICLE 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 Raquel Albero-González 1 & Silvia Hernández-Llodrà 2 & Nuria Juanpere 1,2 & Marta Lorenzo 3 & Adrià Lloret 1 & Laura Segalés 2 & Xavier Duran 4 & Lluís Fumadó 5 & Lluís Cecchini 5 & Josep Lloreta-Trull 1,2 Received: 27 December 2018 /Revised: 5 April 2019 /Accepted: 3 June 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract 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. Keywords Mismatch repair genes . Grade groups . ERG . PTEN . Prostate cancer Introduction Mismatch repair (MMR) is an excision-resynthesis system that acts as a DNA damage sensor, correcting mismatches generated during DNA replication. The best known com- plexes are MutSα and MutLα, formed by MSH2 and MSH6, and MLH1 and PMS2, respectively [1–4]. Defects in DNA MMR proteins are permissive for carcinogenesis, giving rise to microsatellite instability (MSI) and conferring a hypermutated status [5]. The role of MMR genes and its proteins has been extensively studied in colorectal [6] and endometrial cancer [7]. There are recent studies on MMR protein expression in prostate tumors [8–16], but the biologic and clinical meaning in this setting is not fully understood. Pritchard et al. [5] described a hypermutated microsatellite- unstable form of advanced prostate cancer (PrCa), associated with MSH2 and MSH6 structural rearrangements. In contrast Raquel Albero-González and Silvia Hernández-Llodrà contributed equally to this work. * Silvia Hernández-Llodrà silvia.hernandez@upf.edu 1 Department of Pathology, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain 2 Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona, Spain 3 Hospital del Mar – Hospital del Mar Medical Research Institute (IMIM), Passeig Marítim 25-29, 08003 Barcelona, Spain 4 Consulting Service on Methodology for Biomedical Research, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain 5 Department of Urology, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain Virchows Archiv https://doi.org/10.1007/s00428-019-02591-z