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MMR Proteins (mmr + protein)
Terms modified by MMR Proteins Selected AbstractsMSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeresAGING CELL, Issue 1 2009Paula Martinez Summary Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerase-deficient mice. In particular, progressively shorter telomeres at successive generations of MSH2,/,Terc,/,- mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2,/,Terc,/, mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway. [source] DNA mismatch repair protein expression and microsatellite instability in primary mucosal melanomas of the head and neckHISTOPATHOLOGY, Issue 6 2007C Marani Aims:, To examine the expression of DNA mismatch repair (MMR) proteins and the presence of microsatellite instability (MSI) in seven primary mucosal melanomas of the head and neck (MMHN). Methods and results:, Haematoxylin and eosin staining and immunohistochemical analysis for routine diagnostic markers and for MMR proteins were performed. Six cases were examined for MSI. Four cases were monomorphous and three cases were pleomorphic type MMHN. Melanocytic markers were positive in all cases. Immunoreactivity for MMR proteins was weak in normal epithelium. The neoplastic tissue in six cases showed positivity for all MMR proteins with different percentages. One case showed weak positivity for hMSH2 and hMSH6 and no immunoreactivity for hMLH1 or hPMS2. Staining intensity was higher in tumour cells than in matched normal mucosa in three cases for hMSH2 and hMLH1 and in two cases for hPMS2. None of the examined cases showed MSI. Conclusions:, Expression of hMSH2 and hMLH1 proteins was up-regulated in three cases, whereas in two cases that of hPMS2 was increased. hMSH6 expression was comparable to that of normal cells in all cases. The percentage of positive neoplastic cells and the intensity of staining seemed to be greater in pleomorphic melanomas. Six cases were MMR-proficient and microsatellite stable. [source] Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes,HUMAN MUTATION, Issue 11 2007Jianghua Ou Abstract Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is caused by DNA variations in the DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and PMS2. Many of the mutations identified result in premature termination of translation and thus in loss-of-function of the encoded mutated protein. These DNA variations are thought to be pathogenic mutations. However, some patients carry other DNA mutations, referred to as unclassified variants (UVs), which do not lead to such a premature termination of translation; it is not known whether these contribute to the disease phenotype or merely represent rare polymorphisms. This is a major problem which has direct clinical consequences. Several criteria can be used to classify these UVs, such as: whether they segregate with the disease within pedigrees, are absent in control individuals, show a change of amino acid polarity or size, provoke an amino acid change in a domain that is evolutionary conserved and/or shared between proteins belonging to the same protein family, or show altered function in an in vitro assay. In this review we discuss the various functional assays reported for the HNPCC-associated MMR proteins and the outcomes of these tests on UVs identified in patients diagnosed with or suspected of having HNPCC. We conclude that a large proportion of MMR UVs are likely to be pathogenic, suggesting that missense variants of MMR proteins do indeed play a role in HNPCC. Hum Mutat 28(11), 1047,1054, 2007. © 2007 Wiley-Liss, Inc. [source] Mismatch repair expression in testicular cancer predicts recurrence and survivalINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Alfredo Velasco Abstract We investigated mismatch repair (MMR) gene expression in testicular cancer as a molecular marker for clinical outcome (recurrence, response to chemotherapy and death) using protein expression and specific genetic alterations associated with the presence or absence of MMR activity. One hundred sixty-two cases of paraffin-embedded testis cancer specimens were subjected to immunohistochemical analysis using monoclonal antibody for MLH1 and MSH2 MMR proteins and genetic analysis using specific polymorphic markers. The degree of MMR immunoreactivity and genetic instability in the form of loss of heterozygosity (LOH) and/or microsatellite instability (MSI) were determined by comparing matched normal and tumor tissue. The degree of immunohistochemical staining for MMR expression was associated with a shorter time to tumor recurrence, resistance to chemotherapy and death. Furthermore, clinical relapse and cancer specific death was also associated with tumors exhibiting a high degree of MSI, p = 0.01 and 0.04, respectively. In contrast, LOH was not associated with recurrence, resistance to chemotherapy or death. Therefore, MMR expression defines testis cancers with distinct molecular properties and clinical behavior, such that tumors with decreased MMR immunostaining and/or increased frequency of MSI have a shorter time to recurrence and death despite chemotherapy. © 2007 Wiley-Liss, Inc. [source] Microsatellite instability and alteration of E2F-4 gene in adenosquamous and squamous cell carcinomas of the stomachPATHOLOGY INTERNATIONAL, Issue 9 2000Dong Kyun Woo Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) is a form of genomic instability underlying the tumorigenesis of various human neoplasms. To evaluate the roles of MSI in the pathogenesis of gastric carcinomas with squamous differentiation, 17 primary stomach cancer patients (15 adenosquamous and two squamous cell carcinomas) were examined for MSI frequency using five microsatellite markers and the criteria for MSI recommended by the National Cancer Institute Workshop. The molecular causes and consequences of MSI in these neoplasms were further researched through the immunohistochemistry of MMR proteins and the mutational analysis of cancer-associated genes targeted by MSI, respectively. Two of the 17 (12%) cases demonstrated MSI at the most examined loci and were classified as having high level MSI (MSI-H). These tumors also exhibited frame-shift mutations at mononucleotide repeats in the target genes, including TGF,RII, IGFIIR, BAX, and hMSH6. It is interesting to note that the mutations of the serine (AGC)13 repeats within the E2F-4 gene were found only in the squamous cell carcinoma portions of them, whereas such alterations were not detected in any of the adenocarcinomatous portions. This suggests that E2F-4 might be implicated in the transformation of adenocarcinoma into squamous cell carcinoma and further studies are needed to understand its role in squamous differentiation. [source] Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancerBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2008L.C. Young Summary Background, In addition to an established role in the repair of postreplicative DNA errors, DNA mismatch repair (MMR) proteins also contribute to cellular responses to exogenous DNA damage. Previously, we have shown that Msh2 -null mice display increased sensitivity to ultraviolet (UV) B-induced tumorigenesis, but squamous cell carcinomas (SCC) generated are microsatellite stable, suggesting a role for MMR other than postreplicative repair in UV-induced cutaneous tumour formation. Objectives, We questioned whether there was evidence of MMR dysfunction in human SCC, thus validating the mouse models of MMR-dependent UVB-induced skin cancer. Methods, Using tissue microarrays we examined both nuclear and cytoplasmic levels of MMR proteins MSH2, MSH6, MSH3, MLH1 and PMS2 in more than 200 cases of cutaneous SCC and basal cell carcinoma (BCC). Results, We found that subsets of these 10 MMR protein measures were increased in nonmelanoma skin cancer (NMSC) compared with normal epidermal samples; this was particularly true of SCC. In fact, based on post hoc tests and MMR protein distribution patterns, BCC was distinct from SCC. With the exception of nuclear MSH2, the BCC had lower levels of identified MMR protein measures than SCC. We believe this to be important because not only is SCC more aggressive than BCC, but evidence suggests that these two NMSC subtypes arise through different molecular pathways. Conclusions, In combination with previously established roles for MMR proteins in response to UVB-induced DNA damage, our data point towards an expanded perspective of the importance of MMR proteins in the suppression of UVB-induced tumorigenesis and, potentially, tumour behaviour. [source] Selecting patients with young-onset colorectal cancer for mismatch repair gene analysis,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 12 2007M. Walker Background: Young patients with colorectal cancer are at increased risk of carrying a germline mutation in mismatch repair (MMR) genes. This study investigated the role of clinical criteria and immunohistochemistry for MMR proteins in selecting young patients for mutation testing. Methods: A cohort of 56 consecutive patients with colorectal cancer aged less than 45 years were stratified into three groups based on clinical criteria: ,Amsterdam criteria', ,high risk' and ,young onset only'. Immunohistochemistry for four MMR proteins was carried out and the rate of compliance with clinical guidelines determined. Results: Tumours from 11 patients (20 per cent) had abnormal MMR protein expression, of whom eight were referred for genetic assessment. Of 21 patients (38 per cent) in total referred to the genetics unit, six MMR gene mutations were identified, all associated with abnormal immunohistochemistry. Conclusion: MMR immunohistochemistry should be considered routine in young-onset colorectal cancer. Copyright © 2007 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||