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Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients.
J Pathol. 2000 Nov; 192(3):328-35.JP

Abstract

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.

Authors+Show Affiliations

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. W.J.F.de_Leeuw@Pathology.Medfac.Leidenuniv.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11054716

Citation

de Leeuw, W J., et al. "Prediction of a Mismatch Repair Gene Defect By Microsatellite Instability and Immunohistochemical Analysis in Endometrial Tumours From HNPCC Patients." The Journal of Pathology, vol. 192, no. 3, 2000, pp. 328-35.
de Leeuw WJ, Dierssen J, Vasen HF, et al. Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol. 2000;192(3):328-35.
de Leeuw, W. J., Dierssen, J., Vasen, H. F., Wijnen, J. T., Kenter, G. G., Meijers-Heijboer, H., Brocker-Vriends, A., Stormorken, A., Moller, P., Menko, F., Cornelisse, C. J., & Morreau, H. (2000). Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. The Journal of Pathology, 192(3), 328-35.
de Leeuw WJ, et al. Prediction of a Mismatch Repair Gene Defect By Microsatellite Instability and Immunohistochemical Analysis in Endometrial Tumours From HNPCC Patients. J Pathol. 2000;192(3):328-35. PubMed PMID: 11054716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. AU - de Leeuw,W J, AU - Dierssen,J, AU - Vasen,H F, AU - Wijnen,J T, AU - Kenter,G G, AU - Meijers-Heijboer,H, AU - Brocker-Vriends,A, AU - Stormorken,A, AU - Moller,P, AU - Menko,F, AU - Cornelisse,C J, AU - Morreau,H, PY - 2000/10/31/pubmed PY - 2001/3/3/medline PY - 2000/10/31/entrez SP - 328 EP - 35 JF - The Journal of pathology JO - J. Pathol. VL - 192 IS - 3 N2 - Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes. SN - 0022-3417 UR - https://www.unboundmedicine.com/medline/citation/11054716/Prediction_of_a_mismatch_repair_gene_defect_by_microsatellite_instability_and_immunohistochemical_analysis_in_endometrial_tumours_from_HNPCC_patients_ L2 - https://doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH701>3.0.CO;2-2 DB - PRIME DP - Unbound Medicine ER -