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Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases.
Cancer Res 2009; 69(17):7053-61CR

Abstract

An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2, MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1 methylation, indicating that sporadic cases can be admixed in with Lynch syndrome cases, even those meeting the strongest criteria for Lynch syndrome. MMR gene defects were found in similar frequency in cases where tumors were and were not available. One MLH1 and one MSH2 deletion mutation were found in MSI-stable/low cases, indicating that MSI testing can exclude cases with pathogenic mutations. Our analysis supports a diagnostic algorithm where cases are selected for analysis based on clinical criteria or prediction models; isolated sporadic young-onset cases can be prescreened by tumor testing, whereas familial cases may be directly subjected to molecular analysis for mutations in MMR genes followed by MSI, protein expression, and DNA methylation analysis to aid in the resolution of mutation-negative cases.

Authors+Show Affiliations

Ludwig Institute for Cancer Research, Department of Medicine, Biomedical Sciences Graduate Program, University of California at San Diego School of Medicine, La Jolla, California 92093-0669, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19690142

Citation

Mueller, James, et al. "Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (hereditary Nonpolyposis Colorectal Cancer) Cases." Cancer Research, vol. 69, no. 17, 2009, pp. 7053-61.
Mueller J, Gazzoli I, Bandipalliam P, et al. Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. Cancer Res. 2009;69(17):7053-61.
Mueller, J., Gazzoli, I., Bandipalliam, P., Garber, J. E., Syngal, S., & Kolodner, R. D. (2009). Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. Cancer Research, 69(17), pp. 7053-61. doi:10.1158/0008-5472.CAN-09-0358.
Mueller J, et al. Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (hereditary Nonpolyposis Colorectal Cancer) Cases. Cancer Res. 2009 Sep 1;69(17):7053-61. PubMed PMID: 19690142.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. AU - Mueller,James, AU - Gazzoli,Isabella, AU - Bandipalliam,Prathap, AU - Garber,Judy E, AU - Syngal,Sapna, AU - Kolodner,Richard D, Y1 - 2009/08/18/ PY - 2009/8/20/entrez PY - 2009/8/20/pubmed PY - 2009/11/18/medline SP - 7053 EP - 61 JF - Cancer research JO - Cancer Res. VL - 69 IS - 17 N2 - An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2, MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1 methylation, indicating that sporadic cases can be admixed in with Lynch syndrome cases, even those meeting the strongest criteria for Lynch syndrome. MMR gene defects were found in similar frequency in cases where tumors were and were not available. One MLH1 and one MSH2 deletion mutation were found in MSI-stable/low cases, indicating that MSI testing can exclude cases with pathogenic mutations. Our analysis supports a diagnostic algorithm where cases are selected for analysis based on clinical criteria or prediction models; isolated sporadic young-onset cases can be prescreened by tumor testing, whereas familial cases may be directly subjected to molecular analysis for mutations in MMR genes followed by MSI, protein expression, and DNA methylation analysis to aid in the resolution of mutation-negative cases. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/19690142/Comprehensive_molecular_analysis_of_mismatch_repair_gene_defects_in_suspected_Lynch_syndrome__hereditary_nonpolyposis_colorectal_cancer__cases_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19690142 DB - PRIME DP - Unbound Medicine ER -