An Evaluation of the Immunohistochemical Expression of Mismatch Repair Proteins (MSH2, MSH6, MLH1, and PMS2) in Prostate Adenocarcinoma

Abstract

Background and objectiveMismatch repair (MMR) proteins are an integral part of the cell cycle, and they play an important role in the genomic stability of the microsatellite complex. Microsatellite instability (MSI) is associated with Lynch and multi-tumor syndromes. Identifying patients with Lynch syndrome is essential for screening, early detection, and surveillance of other Lynch syndrome-associated tumors. The role of MMR deficiency is well known in colorectal and endometrial adenocarcinoma. However, the role of MMR deficiency in prostatic adenocarcinoma is a matter of controversy. A few studies have been published to analyze the association between MMR deficiency and prostatic adenocarcinoma. In this study, we used immunohistochemistry to look into the expression of four MMR proteins in prostatic adenocarcinoma: MSH2, MSH6, MLH1, and PMS2. MethodologyThis was a cross-sectional descriptive study involving 74 cases of acinar prostatic adenocarcinoma, diagnosed with hematoxylin & eosin (H&E), over a period of six months between December 2021 and May 2022 at the Chughtai Institute of Pathology in Lahore, Pakistan. We performed the immunohistochemical (IHC) analysis and interpretation of four antibodies, i.e., MSH2, MSH6, MLH1, and PMS2. ResultsIn our study, the age of the patients ranged from 50 to 98 years, with a mean age of 67.99 ± 9.59 years. The specimens were collected through transurethral resection of the prostate (TURP), transurethral vaporization of the prostate (TVP), core biopsy, and radical prostatectomy. Isolated loss of each MSH2 and PMS2 was noted in nine cases (12.20%) and MSH6 in two cases (2.70%). There was no loss noted for MLH1. Furthermore, simultaneous loss of MSH2/MSH6 was observed in one case (1.35%). ConclusionOur study findings revealed a low frequency of IHC expression of MMR proteins, especially the concurrent loss of paired MMR proteins. However, prostatic adenocarcinoma is associated with the isolated loss of MMR proteins. Thus, the present study does not warrant reflex testing/screening in every case of prostatic adenocarcinoma, because of its low frequency, which is probably suggestive of its sporadic pattern.

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

“…MSH6 alterations have been reported in approximately 1% of PC cases [42,[59][60][61]. A loss of the immunohistochemical expression of MSH6 was found in 2.7-16.8% of PCs [48,49]. However, Alberto-Gonzalez et al, in their study, revealed MSH6 overexpression in 42.1% of the cases [62].…”

“…Another study found PMS2 mutations in 0.4% of metastatic PC patients [59]. However, Sharma M. et al and Javeed S. et al, in their studies, revealed a loss of PMS2 expression in 12.3% and 12.2% of PCs, respectively [48,49]. Although MMR gene alterations are associated with a worse prognosis in PC patients, there are no exact data correlating the PC grade with PMS2 expression [63].…”

“…MLH1 is an essential component of the MMR system, and its alterations have been associated with MSI and the development of various cancers [46], including increased PC risk [47]. In PC, MLH1 alterations are relatively rare, with a reported loss of MLH1 expression in 0-0.9% of PCs [48,49]. However, in a study by Khan HM et al in men aged over 75, PCs with a MLH1 mutation had a cumulative incidence of 13.8% [50].…”

“…MSH2 alterations have also been identified in PC patients. The reported prevalence of MSH2 alterations is estimated to be 1-2% in mCRPC [32,42,56], and a loss of MSH2 expression is estimated to occur in 2.7-12.2% of PCs [48,49]. These alterations include point mutations, deletions, and rearrangements, resulting in a loss of MSH2 protein expression and impaired MMR function [57].…”