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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

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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.

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Conflict of interest

The authors declare that they have no conflict of interest.

Funding

The study has been funded with grants Jordi Gras 2016-2017 from the Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) and FIS/Instituto Carlos III/PI15/FEDER PI15/00452 from the Spanish Ministry of Health. The authors thank the Parc de Salut MAR Biobank (MARBiobanc), Barcelona, Spain, for the archival support.

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  1. Raquel Albero-González and Silvia Hernández-Llodrà contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain

    Raquel Albero-González, Nuria Juanpere, Adrià Lloret & Josep Lloreta-Trull

  2. Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Silvia Hernández-Llodrà, Nuria Juanpere, Laura Segalés & Josep Lloreta-Trull

  3. Hospital del Mar – Hospital del Mar Medical Research Institute (IMIM), Passeig Marítim 25-29, 08003, Barcelona, Spain

    Marta Lorenzo

  4. Consulting Service on Methodology for Biomedical Research, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain

    Xavier Duran

  5. Department of Urology, Hospital del Mar-Parc de Salut Mar-IMIM, Barcelona, Spain

    Lluís Fumadó & Lluís Cecchini

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  1. Raquel Albero-González
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Contributions

RA-G, NJ, ML, ALl, LF, LC, and JLl-T contributed to specimen preparation and clinical data acquisition. JLl-T and SH-Ll designed the research study. RA-G, NJ, ALl, LS, and JLl-T participated in the pathological data management and staining evaluation. ML constructed and stained the tissue microarrays. XD and SH-Ll performed the statistical analysis. RA-G, SH-Ll, and JLl-T participated in the data preparation and analysis and wrote the paper. All authors have read and approved the final version of the manuscript.

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Correspondence to Silvia Hernández-Llodrà.

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Albero-González, R., Hernández-Llodrà, S., Juanpere, N. et al. 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. Virchows Arch 475, 223–231 (2019). https://doi.org/10.1007/s00428-019-02591-z

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