Up-regulation of mismatch repair genes MSH6, PMS2 and MLH1 parallels development of genetic instability and is linked to tumor aggressiveness and early PSA recurrence in prostate cancer

Abstract

DNA mismatch repair (MMR) is integral to the maintenance of genetic stability. We aimed to evaluate the clinical impact of MMR gene expression in prostate cancer. The MMR genes MSH6, MLH1 and PMS2 were analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with ETS-related gene status and deletions of PTEN, 3p13, 5q21 and 6q15. MSH6, MLH1 and PMS2 expression was detectable in 89.5%, 85.4% and 85.0% of cancers and was particularly strong in cancers with advanced pathological tumor stage (P < 0.0001 each), high Gleason grade (P < 0.0001 each), nodal metastasis (P ≤ 0.0083) and early biochemical recurrence (P < 0.0001). High levels of MMR gene expression paralleled features of genetic instability, such as the number of genomic deletions per cancer; strong expression of all three MMR genes was found in 24%, 29%, 30%, 33% and 42% of cancers with no, one, two, three or four to five deletions (P < 0.0001). The prognostic value of the analyzed MMR genes was largely driven by the subset of cancers lacking ERG fusion (P < 0.0001), while the prognostic impact of MMR gene overexpression was only marginal in ERG-positive cancers. Multivariate analyses suggested an independent prognostic relevance of MMR genes in ERG-negative prostate cancers when compared with prognostic parameters available at the time of initial biopsy. In conclusion, MMR overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. ERG fusion should be analyzed along with MMR gene expression in potential clinical tests.

Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion

“…First, it is possible that APE1—as a DNA repair enzyme—is activated in case of genomic alterations such as TMPRSS2‐ERG fusions. In earlier studie we have repeatedly found markedly increased expression levels of mismatch (MMR) or double strand breakage repair (DSB) genes in cancers with ERG fusions . However, in contrast to these MMR/DSB repair genes, APE1 overexpression was not universally associated with presence of chromosomal deletions.…”

“…45 Our data demonstrate markedly higher APE1 expression levels in genes in cancers with ERG fusions. 46 However, in contrast to these MMR/DSB repair genes, APE1 overexpression was not universally associated with presence of chromosomal deletions. The main function of APE1 as a base excision repair gene is consistent with only a minor role in DSB repair in this case.…”

Genomic Instability Promoted by Overexpression of Mismatch Repair Factors in Yeast: A Model for Understanding Cancer Progression

“…MMR proteins are often overexpressed in cancers, and in some cases this overexpression has been correlated with genome instability (summarized in Table S1; Velasco et al 2002;Kauffmann et al 2007;Li et al 2008;Wagner et al 2016;Wilczak et al 2017). These observations encouraged us to compare expression levels of MMR genes, using data available in cancer databases such as TCGA and GENT (Shin et al 2011).…”

“…1. In a study of 11,152 prostate cancer specimens, Wilczak et al (2017) observed that MSH6, MLH1, and PMS2 expression were high in cancers with advanced pathological tumor stage, high Gleason grade, nodal metastasis, and early biochemical recurrence. They also found that high levels of MMR gene expression paralleled features of genetic instability, such as the number of genomic deletions per cancer.…”

“…Levels of MMR proteins such as MSH2, MSH6, MLH1, PMS2, and EXO1 are often increased in a variety of cancers, and are correlated with high levels of genomic instability that include genomic deletions and MSI, increased tumor aggressiveness, increased cancer recurrence, and poor survival (Velasco et al 2002;Kauffmann et al 2007;Li et al 2008;Wagner et al 2016;Wilczak et al 2017). However, a causeeffect relationship between these deleterious characteristics and increased levels of MMR proteins has not been established.…”