Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation
Sharlene GillNoralane M. LindorLawrence J. BurgartRegenia L. SmalleyOlga LeontovichAmy J. FrenchRichard M. GoldbergDaniel J. SargentJeremy R. JassJohn L. HopperMark A. JenkinsJoanne YoungMelissa BarkerMichael D. WalshAndrew RuszkiewiczStephen N. Thibodeau
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Abstract Purpose: Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype. Experimental Design: Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history. Results: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer. Conclusions: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.Keywords:
PMS2
MSH6
MSH2
MLH1
Microsatellite Instability
Lynch Syndrome
Introduction Microsatellite instability (MSI), referred to as variations at microsatellite loci, at mismatch repair (MMR) genes leads to the formation of an aberrant MMR system that fails to rectify errors occurring during DNA replication. MMR deficiency can be assessed by immunohistochemical analysis of the expression of mismatch repair proteins in the target tissues. Methods We investigated the expression of four key MMR proteins (MLH1, MSH2, MSH6, and PMS2) in formalin-fixed paraffin-embedded (FFPE) tumor and normal tissues obtained from thirty gastric cancer (GC) patients. The association of clinicopathological features with MMR status was also analyzed. Results A total of 12 (40%) GC patients exhibited loss of expression of MMR proteins, including loss of MLH1 and PMS2 in 3 cases and loss of MSH2 and MSH6 in 4 cases. Univariate analysis showed an association of loss of MMR protein expression with moderately differentiated GC. However, there was no statistically significant association between loss of MMR protein expression with gender, tumor location, depth of invasion, lymph node metastasis, WHO classification, lympho-vascular invasion, and infection with H. pylori. Conclusion Our results implicate the role of mismatch repair proteins in gastric tumorigenesis. The MMR protein status is an important aspect of tumorigenesis and can be prescribed for the screening of GC.
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The MMR (DNA mismatch repair) system helps to maintain the integrity of the genome. This involves eliminating base-base mismatches and insertion/deletion loops, which can lead to microsatellite instability, as seen in tumour cells. Hereditary non-polyposis colon cancer is the result of dominant mutations in MMR genes, such as MLH1, MSH2 and MSH6. More recently there have been case reports of biallelic mutations in the MMR genes MLH1, MSH2 and PMS2. These result in a distinct autosomal recessive cancer predisposition syndrome. The syndrome is characterized by childhood haematological malignancies, brain tumours and the presence of café au lait patches. Second primaries occur frequently in this condition, and survival into adulthood is rare.
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Lynch syndrome (LS), the most common form of familial CRC predisposition that causes tumor onset at a young age, is characterized by the presence of microsatellite instability (MSI) in tumors due to germline inactivation of mismatch repair (MMR) system. Two MMR genes namely MLH1 and MSH2 account for majority of LS cases while MSH6 and PMS2 may account for a minor proportion. In order to identify MMR genes causing LS in India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS patient colorectal tumor samples. Though a majority exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and MLPA-based mutation and exonic deletion/duplication screening respectively, revealed genetic lesions in samples with and without MMR gene expression. Interestingly, tumor samples with and without MMR expression exhibited significant differences with respect to histological (mucin content) and molecular (instability exhibited by mononucleotide microsatellites) features. The study has revealed for the first time a significant proportion of LS tumors not exhibiting loss of MMR expression.
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Introduction: Colorectal cancer is the third most common cancer worldwide. Microsatellite instability (MSI) contributes to be one of the main mechanisms in colorectal cancer. Individuals with MSI tumors have loss of expression of one or more Mismatch Repair proteins. MSI tumors have better survival rate than microsatellite stable (MSS) tumors, poor response to 5FU-based adjuvant chemotherapy and relatively successful immunotherapy in metastatic MSI tumors. Immunohistochemistry recognizes altered gene by recognizing loss of its protein product. Based on the presence or absence of Mismatch repair proteins, groups are classified into Mismatch repair proficient (MMR-p) and Mismatch repair deficient (MMR-d). Aim: To investigate the immunohistochemical profile of Mismatch repair proteins namely: hMLH1, hMSH2, hMSH6, and hPMS2 in surgically resected colorectal cancer specimens. Materials and Method: A total of 76 cases were selected from the Histopathology Department of HTAA to determine MMR protein expression status. Cases were either MMR-p or MMR-d. Results: Of the specimens which were properly immunostained, seventeen out of seventy-six cases (22.37%) showed loss of one or more MMR proteins expression and thus were MMR-d. MLH1, MSH2, MSH6 and PMS2 protein expression was detected as 85.53% (65/76), 81.6% (62/76), 88.16% (67/76), and 76.32% (58/76), respectively. Conclusion: Mismatch repair proteins profile should be done using immunohistochemistry in local laboratories on these selected cases before referring for the expensive molecular test.
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Background: DNA mismatch repair (MMR) is an important process during the DNA replication for correcting DNA replication errors. Deficient MMR (dMMR) leads to increased mutational burden and has been associated with several carcinomas and cancer syndromes like Lynch syndrome. The absence of MMR protein by immunohistochemistry is a surrogate marker for microsatellite instability. The aim of the study is to present our datas of MMR deficient tumors and the pattern of MMR protein loss by using immunohistochemistry,also to highlight the technical issues of tissue processing that interfere in result interpretation. Material & Method: 318 cases of various carcinomas were analysed for mismatch repair proteins viz. MLH1, MSH2, MSH6 and PMS2 using immunohistochemistry.Result: Out of total 318 cases,47 cases showed deficient MMR proteins. Among the MMR deficient cases colonic adenocarcinoma cases has the highest percentage with loss of MMR proteins. Regarding pattern of MMR protein loss the simultaneous loss of both MLH1 and PMS2 is the most common pattern. In 5 cases (1.5%) of total cases we could not interpret the result. In compare to MMR proficient colorectal adenocarcinomas, the MMR deficient tumors are predominantly right sided and on histopathology they shows high grade histology,intratumoral lymphocytic infiltration, peritumoral lymphocytic infilatration,,mucinous and signet cell components. Conclusion: Evaluation of MMR proteins using immunohistochemistry is relatively easy to institute in the routine testing as it is a useful predictive and prognostic marker in various carcinomas,also it helps screening the cases of lynch syndrome. This study also highlight the need of using standard protocols for tissue fixation and processing before evaluating for MMR proteins.
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Colorectal cancer (CRC) is highly prevalent throughout the world and represents the 3rd most common cancer in men and the 2nd in women worldwide. Microsatellite instability (MSI) is a term used to denote a hypermutable phenotype caused by the loss of DNA mismatch repair (MMR) activity, and is a phenomenon now linked to the pathways of colorectal carcinogenesis. Compounding its importance is its integral association with Lynch syndrome, the most common cause for CRCs in young individuals. In the present study, we aimed to analyse the proportion of patients with risk of microsatellite instability by checking for loss of immunostaining for mismatch repair (MMR) proteins. From January 2016 to December 2016 and May 2017 to October 2017, 40 consecutive newly diagnosed cases of colorectal cancer were included in the study. The expression of MMR proteins in the tumour tissue using IHC for MSH2, MSH6, MLH1 and PMS2 was studied. Among the 40 cases, 3 (7.5%) demonstrated loss of MMR proteins and 37 (92.5%) cases had intact nuclear expression. Out of the three cases with MMR loss, one showed concurrent loss of MLH1 and PMS2, the second showed concurrent loss of MSH2 and MSH6 and the third showed an isolated loss of MSH6. Colorectal carcinomas showing MMR mutations are seen in the Mangalorean population. However, the incidence in our study was relatively low compared to most other studies, probably due to a variation in ethnicity.
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Abstract Lynch syndrome (LS), also called Hereditary Non-Polyposis Colorectal Cancer, the most well studied form of familial CRC, is responsible for about 3% of all CRC cases. LS-associated CRC often exhibits one or more of the following features namely early age of onset, occurrence of synchronous/metachronous tumors, presence of more than one affected family member and tumors predominantly localized to the proximal/right colon with specific clinico-pathological features such as a mucinous histology, poor differentiation and immune infiltration. LS is primarily a disease of defective MisMatch Repair (MMR) and is caused by germline mutational inactivation of any one of four major MMR genes viz. MLH1, MSH2, MSH6 and PMS2. A hallmark of LS-associated tumors is presence of ‘microsatellite instability’ (MSI), a term used to describe frequent occurrence of expanded/contracted microsatellites that arise during DNA replication and are not corrected due to defective MMR. MLH1 and MSH2 account for a majority (up to 90%) of LS cases while MSH6 and PMS2 are involved in a minor proportion. Mutational inactivation of an MMR gene almost always results in loss of corresponding protein expression in the tumor, which can be easily detected by immunohistochemistry. In the first comprehensive study from India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS-associated colorectal tumor samples. Though a majority (85.4%) exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and Multiple Ligation-dependent Probe Amplification based mutation and exonic deletion/duplication screening respectively, revealed MMR gene lesions in 81% of samples exhibiting loss of corresponding MMR protein expression, including thirteen mutations and four exonic rearrangements. Seven novel mutations (four in MLH1 and three in MSH2) were identified. Surprisingly, MMR gene lesions were also detected in a significant proportion (78%) of tumor samples not exhibiting MMR expression loss. Interestingly, samples with and without MMR expression exhibited significant differences with respect to mucinous histology and instability exhibited by specific microsatellites. In addition, MMR negative samples mainly harbored MMR gene in-del or point mutations while MMR positive samples predominantly harbored MMR gene exonic rearrangements. The study has therefore revealed for the first time a significant proportion of suspected LS tumors not exhibiting loss of MMR expression despite harboring MMR gene rearrangements. More importantly, our results indicate significant differences in the biology of LS-associated colorectal tumors occurring due to missense/in-del mutations in MMR genes causing loss of expression and those that occur due to MMR gene exonic rearrangements not resulting in loss of expression. Citation Format: Murali D. Bashyam, Viswakalyan Kotapalli, Ratheesh Raman, Brijesh K. Yadav, Ajay K. Chaudhary, Swarnalata Gowrishankar, Shantveer G. Uppin, Ravikanth Kongara, Regulagadda A. Sastry, Mohana Vamsy, Sujit Patnaik, Shoba Dsouza, Devendra C. Desai, Tester Ashavaid. Identification of MMR gene exonic rearrangements in suspected Lynch syndrome tumors without loss of MMR expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2014-1285
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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.
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