Loss of DNA mismatch repair proteins in prostate cancer.

Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancers, respectively. Loss of at least 1 MMR protein was identified in 50 (22.7%) cases. There were no statistically significant associations between MMR deficiency and patient age, family history of prostate cancer, Gleason score, or pT/pN stage. Nonetheless, the levels of preoperative prostate-specific antigen (PSA) were significantly (P = .015) higher in patients with MMR deficiency (mean ±â€ŠSD: 9.12 ±â€Š9.01 ng/mL) than in those without abnormal MMR (5.76 ±â€Š3.17 ng/mL). There were 15 (6.8%) cases showing loss of at least 2 MMR proteins, which was not significantly associated with PSA level or tumor grade/stage. Additionally, 5 and 2 cases showed losses of at least 3 MMR proteins and all 4 proteins, respectively. Kaplan-Meier analysis revealed no significant associations between loss of MLH1 (P = .373), MSH2 (P = .348), MSH6 (P = .946), or PMS2 (P = .681), or at least 1 (P = .477), 2 (P = .486), or 3 (P = .352) MMR proteins and biochemical recurrence. Further analyses of the data on programmed death-ligand 1 (PD-L1) expression previously stained in the same set of tissue microarray demonstrated associations between loss of ≥2 MMR proteins and a higher rate of PD-L1 expression in cancer cells (17.2% vs 5.2%; P = .033) as well as between cases showing both loss of ≥1 MMR protein(s) and PD-L1 expression in tumor-infiltrating immune cells vs a higher risk of biochemical recurrence (P = .045). MMR protein loss was seen in a subset of prostate cancers. Interestingly, it was associated with significantly higher levels of PSA. Moreover, immunohistochemical detection of MMR proteins together with other proteins, such as PD-L1, might be helpful in predicting tumor recurrence following radical prostatectomy.

Clinicopathological and survival characteristic of mismatch repair status in ovarian clear cell carcinoma.

BACKGROUND AND OBJECTIVES: We sought to explore the expression of mismatch repair (MMR) status and its correlation with clinicopathologic and survival characteristics in ovarian clear cell carcinoma (OCCC). METHODS: Expression of four MMR proteins (MLH1, PMS, MSH2, and MSH6) were measured using tissue microarray-based immunohistochemistry in 120 OCCC patients. The associations of clinicopathologic parameters with recurrence-free survival (RFS) and overall survival (OS) were analyzed by the Kaplan-Meier method, and multivariate analysis was further performed by the Cox regression model. RESULTS: Overall, 120 OCCC patients met the entry criteria, and their MMR status was detected, consisting of 24 patients with dMMR and 96 patients with proficient MMR (pMMR). Patients with dMMR were strongly associated with platinum-sensitive disease (P = .006) and large tumor volume (P = .038). Among all the patients who have received surgery, tumors with dMMR had a better RFS and OS than those with pMMR (hazard ratio [HR] for recurrence: 0.459 [95% confidence interval {95% CI} = 0.224-0.940], P = .029; HR for death: 0.381 [95% CI = 0.170-0.853], P = .015). In subgroup analysis, dMMR patients experienced a better trend of RFS (HR = 0.273; P = .055) and OS (HR = 0.165; P = .040) than pMMR cases among early stages (I-II), but this difference was not observed in advanced stage (III-IV) patients. Meanwhile, pMMR was associated with a more favorable trend of prognosis than dMMR in platinum-resistant patients (RFS: HR = 0.317, P = .051; OS: HR = 0.370, P = .046). Multivariate analysis revealed that only advanced stages (III-IV) were adverse independent prognosticators for both RFS (HR = 5.938 [95% CI = 2.804-12.574]; P < .001) and OS (HR = 6.209 [95% CI = 2.724-14.156]; P < .001). CONCLUSION: Tumors with dMMR were related to better OS in OCCC on univariate analysis. Only the tumor stage was an independent prognosticator for both RFS and OS. MMR status is a potentially valuable prognostic index in OCCC patients, and larger prospective studies are required to validate its prognostic role.

Enhanced Tumoral MLH1-Expression in MLH1-/PMS2-Deficient Colon Cancer Is Indicative of Sporadic Colon Cancer and Not HNPCC.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is caused by germline mutations of mismatch-repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. MLH1-/PMS2-deficient colorectal carcinomas might be HNPCC-associated but also caused by MLH1-promoter methylation in sporadic colon carcinoma. This study analyzed semiquantitatively whether the MLH1 staining pattern might be indicative of sporadic or HNPCC-associated colorectal cancer. Using a semiquantitative score ranging from 0 (negative) to 12 (maximum immunopositivity) we analyzed MLH1 expression patterns in 130 MLH1-/PMS2-deficient colorectal cancers. The collective consisted of 70 HNPCC-associated colorectal cancers and 60 sporadic colon cancers. In tumor cells of 70 HNPCC-associated colorectal cancers, 64 cases (91.43%) showed no MLH1 staining, 5 cases weak (7.14%) and 1 case (1.43%) stronger staining intensity. In contrast, in tumor cells of 60 sporadic colorectal cancers 45 cases (75.0%) showed no MLH1 staining, 10 cases weak (16.67%) and 5 cases (8.33%) stronger staining intensity to a varying extent. In immunopositive cases, MLH1 showed a characteristic dot-like nuclear staining pattern in the tumor cells. We compared cases with absent to weak MLH1-staining (immunoscores 0 to 2) to cases with elevated immunoscores (3 to 12) detecting a statistically significant difference between HNPCC-associated and sporadic colon cancers (p value = 0.0031, Fisher's exact test). Taken together, enhanced tumoral MLH1 expression in MLH1-/PMS2-deficient colorectal carcinomas seems to be indicative of sporadic origin. In contrast, HNPCC-associated colorectal cancer showed absent or very weak MLH1 immunopositivity. Therefore, this semiquantitative and easy to exert MLH1 immunoscore might help to identify sporadic MLH1-/PMS2-deficient colorectal cancer cases prior to time-consuming methylation analysis.

Incidence of Mismatch Repair Protein Deficiency and Associated Clinicopathologic Features in a Cohort of 104 Ovarian Endometrioid Carcinomas.

Patients with Lynch syndrome have up to a 24% risk of developing ovarian carcinoma, but universal mismatch repair (MMR) protein testing of ovarian carcinomas is not standard practice in most institutions. We reviewed 104 unselected ovarian endometrioid carcinomas (OEC) for various clinicopathologic features to determine if any are predictive of MMR loss. Immunohistochemistry for all 4 MMR proteins was performed followed by MLH1 promoter methylation analysis when indicated. Overall, patients had a mean age of 55 years and tumors averaged 12 cm. Most (72%) patients had stage I tumors, 63% were grade 1, and 30% had a synchronous stage IA endometrial endometrioid carcinoma. Peritumoral lymphocytes and intratumoral stromal inflammation were rare, but tumor-infiltrating lymphocytes averaged 47/10 high-power fields. Endometriosis was noted in 71%, adenofibromatous background in 14%, and both in 14% of tumors. Metaplastic changes were common and included squamous metaplasia (63%), clear cell change (32%), mucinous differentiation (24%), and sex cord-like elements (13%). When follow-up was available (n=99), 78% of patients were alive and well, 12% died from disease, 6% died from other causes, and 4% were alive with disease. Unmethylated, MMR-deficient OECs were identified in 7% of the cohort and included MSH2/MSH6 (n=4), MSH6 (n=2), and PMS2 (n=1). All these tumors were stage I, 71% grade 1, and 57% had a synchronous endometrial endometrioid carcinoma. Among patients in this group with follow-up (n=5), all were alive without evidence of disease (mean 150 mo). Given that no clinicopathologic features were associated with MMR deficiency on univariate analysis, this study highlights the importance of universal MMR screening in OECs.

Endometrial Cancer Presentation and Outcomes Based on Mismatch Repair Protein Expression From a Population-Based Study.

OBJECTIVE: There is uncertainty about the prognostic significance of mismatch repair (MMR) deficiency in endometrial cancer. The objective was to evaluate clinical characteristics and outcomes of endometrial cancers based on MMR status within a population-based study. METHODS: This was a retrospective population-based cohort study of all endometrial cancer cases from the Vancouver Coastal Health Authority region, evaluated for 4 MMR proteins using immunohistochemistry from 2012 to 2015. Patients were classified as MMR deficient (dMMR, any MMR protein absent) or MMR proficient (pMMR), Demographics, tumor characteristics, recurrences, and survival rates were compared according to MMR status. RESULTS: There were 892 patients, with 650 pMMR (72.5%) and 242 dMMR tumors. The dMMR group had more endometrioid tumors (87.6% vs 74.0%, P < 0.001), lymphovascular space invasion (43.8% vs 30.8%, P = 0.001), and dedifferentiation (5.9% vs 1.5%, P < 0.001), but fewer grade 1 tumors compared with the pMMR group (31.8% vs 40.8%, P < 0.001). Median progression-free survival and overall survival have not been reached. After a median follow-up of 31 months (1-99 months), there was no difference in progression or recurrence rates between pMMR and dMMR tumors (19.5% vs 16.5%; P = 0.31). However, among those with nonendometrioid tumors, recurrence and mortality rates were significantly higher for pMMR than dMMR tumors (42.0% vs 10.0%, P = 0.001, and 36.1% vs 13.1%, P = 0.01, respectively), despite similar stage and lymphovascular space invasion distributions. DISCUSSION: In this population-based study, there were no significant differences in recurrence or survival outcomes according to MMR status in endometrial cancer. However, among those with nonendometrioid tumors, there were lower recurrence and mortality rates associated with MMR-deficient compared with MMR-proficient tumors.

Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients.

Lynch syndrome (LS) is an autosomal-dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and is associated with increased risk for various cancers, particularly colorectal cancer and endometrial cancer (EC). Women with LS account for 2% to 6% of EC patients; it is clinically important to identify LS in such individuals for predicting and/or preventing additional LS-associated cancers. PMS2 germline mutation (PMS2-LS) is the rarest contribution to LS etiology among the 4 LS-associated MMR germline mutations, and its detection is complicated. Therefore, prudent screening for PMS2-LS is important as it leads to an efficient LS identification strategy. Immunohistochemistry is recommended as a screening method for LS in EC. Isolated loss of PMS2 (IL-PMS2) expression is caused not only by PMS2-LS but also by MLH1 germline mutation or MLH1 promoter hypermethylation (MLH-PHM). This study aimed to determine the association between MLH1-PHM and IL-PMS2 to avoid inappropriate genetic analysis. We performed MLH1 methylation analysis and MLH1/PMS2 germline mutation testing on the IL-PMS2 cases. By performing MMR-immunohistochemistry on 360 unselected ECs, we could select 8 (2.2%) cases as IL-PMS2. Heterogenous MLH1 staining and MLH1-PHM were detected in 4 of 8 (50%) IL-PMS2 tumors. Of the 5 IL-PMS2 patients who underwent genetic analysis, 1 had PMS2 germline mutation with normal MLH1 expression (without MLH1-PHM), and no MLH1 germline mutation was detected. We suggest that MLH1 promoter methylation analysis for IL-PMS2 EC should be performed to exclude sporadic cases before further PMS2 genetic testing.

Microsatellite instability in stage II colorectal cancer: An Indian perspective.

INTRODUCTION: Around 80% of colorectal carcinoma are associated with chromosomal instability (CIN) while rest of 20 % are euploid, possessing defect in mis match repair system (MMR) quintessential for surveillance and correction of errors in introduced into microsatellites. MATERIALS AND METHODS: We analyse all stage II CRC for MSI who presented at MDTC at Army hospital (research and refrral) new delhi during last 2 years (Jan 14 to Dec 2015). RESULTS: We found that 22.2% patients out of 45 patients with stageII CRC being MSI-. high. We also noticed all suchcases were associated with loss of expression of PMS2 & MLH1, that was in contrast other studies where loss of MLH1 and MSH@, MSH6 were seen more commonly. CONCLUSION: MSI occurs in a significant proportion of colorectal cancers in young (<50 years old) patients. Young age at colorectal cancer diagnosis, proximal tumor location, family history of colorectal cancer were independent predictors of MSI status in our patients. In a proportion of these young patients with MSI tumors, loss of expression of proteins by 2 MMR genes PMS2 and hMLH1 has been identified.