[Mismatch repair protein expression of colorectal cancer: a retrospective analysis of 3 428 cases].
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Abstract:
Objective: To analyze the expression of mismatch repair (MMR) proteins in colorectal cancers (CRC) and to evaluate the feasibility and potential pitfalls of immunohistochemistry (IHC) analysis for MMR. Methods: The IHC sections for MMR proteins were reviewed in 3 428 cases of resected CRC without neoadjuvant therapy at Tianjin Medical University Cancer Institute and Hospital from July 2014 to October 2018. For the cases with unclear MMR IHC results during the initial review, IHC staining was repeated and microsatellite instability (MSI) analysis was performed. Relationships between the expression of MMR proteins and MSI status as well as the clinicopathological parameters were analyzed. Results: IHC staining for MMR was repeated in 28 (0.8%) cases due to poor quality of original IHC sections. Inconsistent results between the original diagnosis and re-diagnosis were found in 119 (3.5%) cases, mainly resulting from PMS2 and MLH1. Finally, 261 (7.6%) cases of CRC showed mismatch repair deficiency (dMMR), mainly from the deficiency of both MLH1 and PMS2 (43.3%,113/261). In the 14 cases with MSI results, the concordant of MSI and MMR was 13 cases. In the 29 dMMR cases with next generation sequencing (NGS) results, the concordant of MSI-high and dMMR was 93.1%(27/29). The cases with inconsistent results between MSI and MMR showed negative expression of MSH6 or PMS2. Twenty-one CRC showed negative expression of MLH1 and partially positive (or weak positive) expression of PMS2, or negative expression of MSH2 and partially positive (or weak positive) expression of MSH6. Among the 19 cases with MSI results, 16 cases were MSI-high, two cases were MSI-low, and one case was microsatellite stable. Compared with mismatch repair proficiency (pMMR), dMMR was more frequently detected in female patients younger than 50 years old, with family history, at early stage (Ⅰ-Ⅱ) CRC, and in the tumors from right colon,with poor differentiation, or mucinous adenocarcinoma/signet ring cell carcinoma (all P<0.05). Conclusions: At present, IHC staining is a clinically effective and convenient method to detect MMR expression, but the operating process and result assessment remain variable and need to be standardized. MSI analysis can be performed in the difficult-to-evaluate cases for MMR to enhance prognostic evaluation and treatment option.Keywords:
PMS2
MSH6
MLH1
MSH2
Microsatellite Instability
Lynch Syndrome
Pancreatic ductal adenocarcinoma (PDAC) has an ominous prognosis and there are only few treatment options. It is therefore crucial to investigate possible predictive markers that may improve the treatment of this disease. Mismatch repair (MMR) deficiency (d-MMR), meaning MMR protein loss (l-MMR) and/or microsatellite instability (MSI), is predictive of response to immunotherapy, but its frequency has to our knowledge not been elucidated in Scandinavian PDACs. Our aims were to examine the frequency of d-MMR in a Danish cohort of PDACs. We constructed multi-punch tissue microarrays (TMAs) using primary tumor tissue. Immunohistochemistry (IHC) for the DNA MMR proteins MLH1, MSH2, MSH6 and PMS2 was performed, and their expression was evaluated using a scoring system from 0 to 4. If the overall score was between 0-2 or if IHC was inconclusive for technical reasons, IHC on whole-tissue sections and MSI using PCR was performed. A final score of 0, 1-2 or 3-4 defined the tumor as l-MMR, MMR reduced (r-MMR) or MMR proficient. In total, 4/164 (2.4 %), 2/164 (1.2 %) and 3/164 (1.8 %) were l-MMR, r-MMR, or inconclusive based on IHC. MSI testing of these specimens showed that two of the four l-MMR tumors were MSI-high, while the remaining cases were microsatellite stable (MSS). In conclusion, in this study of Danish PDACss, d-MMR was found in a small proportion of the tumors. For these patients, individualized treatment using immunotherapy could be considered.
MSH2
Microsatellite Instability
PMS2
MSH6
Tissue microarray
MLH1
Lynch Syndrome
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To investigate the status of mismatch repair (MMR) and microsatellite instability (MSI) in triple-negative breast cancer (TNBC) and to examine correlations between MMR/MSI status and clinicopathological parameters.We retrospectively collected tissue samples from 440 patients with TNBC and constructed tissue microarrays. Protein expression of MLH1, MSH2, MSH6, and PMS2 was detected by immunohistochemistry (IHC). We also analyzed 195 patient samples using MSI polymerase chain reaction (PCR) testing. Correlations between MSI status and clinicopathological parameters and prognosis were analyzed.The median age of the cohort was 49 years (range: 24-90 years) with a median follow-up period of 68 months (range: 1-170 months). All samples were positive for MLH1, MSH2, MSH6, and PMS2, except for one sample identified as MMR-deficient (dMMR) by IHC, with loss of MSH2 and intact MSH6 expression. MSI PCR revealed no case with high-frequency MSI (MSI-H), whereas 14 (7.2%) and 181 (92.8%) samples demonstrated low-frequency and absence of MSI events, respectively. The dMMR sample harbored low-frequency instability, as revealed by MSI PCR, and a possible EPCAM deletion in the tumor, as observed from next-generation sequencing. No correlations were detected between MMR or MSI status and clinicopathological parameters, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, or survival.The incidence of dMMR/MSI-H is extremely low in TNBC, and rare discordant MSI PCR/MMR IHC results may be encountered. Moreover, MMR/MSI status may be of limited prognostic value. Further studies are warranted to explore other predictive immunotherapy biomarkers for TNBC.
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MSH6
Microsatellite Instability
PMS2
MLH1
Tissue microarray
Triple-negative breast cancer
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Microsatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients.A total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed.Of the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, right-sided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II.A moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.
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Impact of DNA mismatch repair deficiency on relapse rate in early-stage, sporadic colorectal cancer.
415 Background: 15-20% of sporadic colorectal cancers (CRC) are characterized by DNA mismatch repair (MMR) deficiency resulting in the phenomenon of microsatellite instability (MSI). There is evidence that CRC with MSI have a significant better prognosis compared to those with intact MMR. We investigated MMR gene expression in patients (pat.) with CRC and correlated it with early relapse rate. Methods: The study relates to 146 pat. with primary CRC UICC stage 0-II who underwent surgical resection at the Donauspital in Vienna and had a complete follow up of at least 60 months. Expression of the MMR genes MLH1, PMS2, MSH2, MSH6 was detected by immunohistochemical staining. Expression of MMR genes was correlated with pat. and disease characteristics as well as relapse frequency within the first 5 years after diagnosis. Chi-squared test was used to compare the distribution of the given variables between MMR gene proficient and deficient pat. Results: Mean age of the total group was 66.14 years, 45.2% were females and 54.8 males. Localization of the tumor was the colon in 69.2% and the rectum in 30.8% of pat., respectively. 33.6% of diseases were classified as UICC stage 0-I, and 66.4% as UICC stage II. 37/ 146 pat. experienced relapse, mean duration to relapse was 2.17 years. 13.7% of all pat. displayed a MMR deficient state. All MMR deficiencies occurred in the colon, none in rectum tumors. MLH1 was always associated with PMS2 deficiency and occurred in 9.6% of pat. There was a significant difference in sex distribution between the proficient and deficient group with 71.4% females with MLH1/PMS2 deficiency (p= 0.038). MSH2 deficiency was detected in 1 pat. only. MSH6 deficiency occurred in 5.5% of pat., none of the variables was significantly different distributed between the proficient and deficient group. None of the MMR deficiencies correlated with relapse rate. Conclusions: Our data suggest that the supposed better prognosis of MMR deficient compared to proficient pat. might not be explained by a different relapse rate within 5 years from diagnosis. Larger and prospective trials are warranted to elucidate plausible explanations for the proposed survival benefit of a MMR deficient state.
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PMS2
MSH2
Microsatellite Instability
MLH1
Lynch Syndrome
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MSH6
MSH2
MLH1
Lynch Syndrome
Microsatellite Instability
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Background and Objectives: Colorectal cancer (CRC) can be classified as mismatch-repair-deficient (dMMR) with high levels of microsatellite instability (MSI-H), or mismatch-repair-proficient (pMMR) and microsatellite stable (MSS). Approximately 15% of patients have microsatellite instability (MSI). MSI-H tumors are associated with a high mutation burden. Monoclonal antibodies that block immune checkpoints can induce long-term durable responses in some patients. Pembrolizumab is the first checkpoint inhibitor approved in the EU to treat dMMR–MSI-H metastatic CRC. Materials and Methods: Our study assesses the regional variability of MSI-H colorectal cancer tumors in Romania. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumor samples from 90 patients diagnosed with colorectal cancer were collected from two tertiary referral Oncology Centers from Romania. Tissues were examined for the expression loss of MMR proteins (MLH1, PMS2, MSH2, MSH6) using immunohistochemistry or MSI status using polymerase chain reaction (PCR), respectively. Results: MSI-H was detected in 19 (21.1%) patients. MSI-H was located more in ascending colon (36.8% vs. 9.9%, p-value = 0.0039) and less in sigmoid (5.3% vs. 33.8%, p-value = 0.0136) than MSS patients. Most patients were stage II for MSI-H (42.1%) as well as for MSS (56.3%), with significant more G1 (40.9% vs. 15.8%, p-value = 0.0427) for MSS patients. Gender, N stage, and M stage were identified as significant prognostic factors in multivariate analysis. MSI status was not a statistically significant predictor neither in univariate analysis nor multivariate analysis. Conclusion: Considering the efficacy of PD-1 inhibitor in metastatic CRC with MSI-H or dMMR, and its recent approval in EU, it is increasingly important to understand the prevalence across tumor stage, histology, and demographics, since our study displayed higher regional MSI-H prevalence (21%) compared to the literature.
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Microsatellite Instability
PMS2
MSH2
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Lynch Syndrome
Microsatellite Instability
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MLH1
MSH2
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Microsatellite instability (MSI) is the genetic pathway underlying 15% of sporadic colorectal carcinoma (CRC) and hereditary non-polyposis CRC. MSI-H CRC has a distinct clinicopathological characteristic including excess mucin and signet ring component, proximal colon, Crohn's like reaction, lymphocytic infiltration, and better survival.
Microsatellite Instability
MSH6
PMS2
Lynch Syndrome
MSH2
Perineural invasion
Signet ring cell
MLH1
Lymphovascular invasion
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The microsatellite instability (MSI) pathway is found in most cases of hereditary nonpolyposis colorectal cancer (HNPCC) and in 12 % of sporadic colorectal cancer (CRC). It involves inactivation of deoxyribonucleic acid mismatch repair (MMR) genes MLH1, MSH2, PMS2, and MSH6. MMR germline mutation detections are an important supplement to HNPCC clinical diagnosis. It enables at-risk and mutation-positive relatives to be informed about their cancer risks and to benefit from intensive surveillance programs that have been proven to reduce the incidence of CRC. In this study, we analyzed for the first time in Tunisia the potential value of immunohistochemical assessment of MMR protein to identify microsatellite instability in CRC. We evaluate by immunohistochemistry MMR protein expression loss in tumoral tissue compared to positive expression in normal mucosa. Immunohistochemistry revealed loss of expression for MLH1, MSH2, MSH6, and PMS2 in 15, 21, 13, and 15 % of cases, respectively. Here, we report a more elevated frequency of MSI compared to data of the literature. In fact, by immunohistochemistry, 70 % of cases were shown to be MSS phenotype, whereas 30 % of cases, in our set, were instable. Moreover, according to molecular investigation, 71 % of cases were instable (MSI-H) and remaining cases were stable (29 %). Thus, we found a perfect association between MMR immunohistochemical analyses and MSI molecular investigation. Immunohistochemical analysis of MMR gene product expression may allow one to specifically identify MSI phenotype of patients with colorectal carcinomas.
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Microsatellite Instability
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MSH2
Lynch Syndrome
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