Microsatellite Instability and Expression of MLH1 and MSH2 in Normal and Malignant Endometrial and Ovarian Epithelium in Hereditary Nonpolyposis Colorectal Cancer Family Members

Ichikawa, Yoshihito; Lemon, Stephen J.; Wang, Shuhe; Franklin, Barbara; Watson, Patrice; Knezetic, Joseph A.; Bewtra, Chhanda; Lynch, Henry T.

doi:10.1016/s0165-4608(98)00252-0

Cited by 55 publications

(43 citation statements)

References 18 publications

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“…This is consistent with other reports demonstrating a correlation between loss of DNA mismatch repair gene function and the microsatellite instability phenotype. [2][3][4][5] Similarly, other studies have also shown a more frequent loss of hMLH1 expression compared with loss of hMSH2 expression. 2,3,5,25 Despite the importance of hMLH1 in microsatellite instability, the presence of normal hMLH1 expression in 53% of the microsatellite instability-high tumors in our study suggested the involvement of other DNA mismatch repair genes as well, such as hPMS1, hPMS2, hMSH3, and hMSH6.…”

Section: Discussionmentioning

confidence: 99%

“…1 Loss of expression of either hMLH1 or hMSH2 has been described in these tumors and contributed to the development of most microsatellite instability phenotypes. [2][3][4][5] The reported frequency of microsatellite instability in ovarian tumors varies, ranging from 0 to 50%. [6][7][8][9][10][11][12] In large part, this large variation is due to the use of different microsatellite markers and different criteria for defining tumors as microsatellite instability-positive.…”

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Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer

et al. 2004

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Microsatellite instability and loss of heterozygosity has been implicated in ovarian carcinogenesis. The reported frequency of microsatellite instability in human ovarian cancer varies significantly owing to the use of heterogeneous tumor histotypes and various microsatellite markers in different laboratories. In this study, we determined the frequency of microsatellite instability in 74 ovarian endometrioid carcinomas using four microsatellite markers (BAT25, BAT26, D5S346, D17S250), and examined hMLH1 and hMSH2 protein expression. In all, 20% of the tumors were microsatellite instability high (two or more markers showing instability) and 12% were microsatellite instability low (one marker showed instability). Loss of hMLH1 and/or hMSH2 expression was found in nine of 15 microsatellite instability-high tumors. The microsatellite instabilityhigh phenotype tended to occur more frequently in low-grade tumors (P ¼ 0.053), but did not correlate with clinical stage. Totally, 38% of cases also displayed loss of heterozygosity at D17S250; this loss of heterozygosity was associated with high clinical stage (P ¼ 0.097). Our results indicate that both microsatellite and loss of heterozygosity at D17S250 are involved in the development of ovarian endometrioid carcinoma.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer

et al. 2004

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“…DISCUSSION Our study confirms earlier observations that in both endometrial and colorectal cancers from HNPCC carriers loss of MLH1/MSH2 protein is strongly related to the presence of germline mutations in the corresponding MMR genes. [12][13][14][15][16] Based on this strong relation, a role for immunohistochemical analysis of protein expression as a pre-screening for further mutation analysis has been suggested. Our data on endometrial cancers of proven MLH1 and MSH2 carriers support this idea.…”

Section: Msi Analysis and Mutation Analysismentioning

confidence: 99%

“…[12][13][14][15] Similar results have been reported in small numbers of endometrial cancer in MLH1 and MSH2 mutation carriers. [15][16][17] Our aim was to investigate whether the presence of germline mutations in MLH1 or MSH2 can be predicted by the outcome of MLH1 or MSH2 immunohistochemistry in normal and (pre)malignant endometrial samples from different groups of patients. As MSI status of the tumor also has been proposed as a good indicator for MMR gene mutations, we performed MSI analysis in a subgroup of patients, including analysis of the relation between protein expression, the presence of MSI and germline mutation status.…”

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MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer

Berends¹,

Hollema²,

et al. 2001

Int. J. Cancer

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The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n ‫؍‬ 6) or without (n ‫؍‬ 4) a known germline mutation; (II) 15 women from HNPCC families with (n ‫؍‬ 7) or without (n ‫؍‬ 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder, clinically defined by the revised Amsterdam criteria. 1 Colorectal cancer and endometrial cancer are the most common malignancies in HNPCC patients. In these patients, the median age at development of colorectal and endometrial cancer is about 44 and 47 years, respectively. 2-4 Most HNPCC cases can be explained by a germline mutation in one of the DNA mismatch repair (MMR) genes. In humans, 5 MMR genes have been associated with HNPCC: MLH1, MSH2, MSH6, PMS1 and PMS2. With current mutation analysis methods, germline mutations can be detected in approximately 60% of HNPCC kindreds, with Ͼ90% of the mutations in MLH1 or MSH2. 5 The dysfunction of the DNA MMR system causes genetic instability, and this instability has been demonstrated in tumors of HNPCC patients as frequent alterations at loci containing short, repetitive sequences, referred to as microsatellite instability (MSI) or replication errors. 5,6 More than 90% of colorectal tumors and about 75% of endometrial tumors in HNPCC mutation carriers show MSI. 7,8 Therefore...

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“…MSI also affects other epithelial tumors including the stomach, endometrium, and ovary. MSI among endometrial cancers varies from 17% to 32% in sporadic cancers while the frequency increases to more than 75% of those tumors associated with HNPCC [42]. For ovarian cancers, MSI range is detected in up to 50% cases [43].…”

Section: Role Of Mmr In Microsatellite Instabilitymentioning

confidence: 99%

Molecular Mechanisms of Mismatch Repair Genes in Cancer A Brief Review

Shilpa¹,

Lakshmi²

2016

Journal of Proteomics & Genomics

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Cancer, characterized by uncontrolled growth and cell division, has commanded tremendous efforts from the research fraternity in elucidating all plausible pathways that drive a normal cell into the oncogenic pathway. Designing new strategies and protocols for treatment of the disease have been extensively studied yet unsuccessful due to the fact that the diagnosis happens at a very late stage of malignancy that leaves less scope for complete revival and high risk of relapse. Amongst the varied reasons of cancer development, mutations; either inherited in the germ line or arising from changes in DNA sequence of somatic tissues during the life, are the major instigators. These mutations may abnormally enhance the function of protooncogenes, or erase effects of the tumor suppressor gene (TSG) products. Over expressed protooncogenes over-ride cell senescence and silenced TSGs derail the control over cell division and genetic stability. TSGs controlling cell growth are critical; however, genes involving DNA repair systems hold an equally important value in maintaining the cellular integrity and growth. The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The MMR system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops (IDLs) and heterologies generated during DNA replication and recombination. Failure to accomplish these functions may lead to cancer and are associated with tumor prone phenotypes. MMR proteins coordinate a complex network of physical and functional interactions and are also involved in activation of cell-cycle check point and induction of apoptosis during DNA damage. They also play a role in cell death by alkylating agents and other chemotherapeutic drugs. Inactivation of MMR genes by mutations or epigenetic silencing in hereditary and sporadic cancers is associated with mutator phenotype and inhibition of apoptosis. A deeper understanding of the molecular mechanism and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies. Introduction Molecular Mechanisms of Mismatch Repair Genes in Abstract

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Microsatellite Instability and Expression of MLH1 and MSH2 in Normal and Malignant Endometrial and Ovarian Epithelium in Hereditary Nonpolyposis Colorectal Cancer Family Members

Cited by 55 publications

References 18 publications

Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer

Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer

MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer

Molecular Mechanisms of Mismatch Repair Genes in Cancer A Brief Review

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