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Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations.
Cancer Lett. 2007 Apr 08; 248(1):89-95.CL

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease with high penetrance, caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 and MLH3. Most reported pathogenic mutations are point mutations, comprising single base substitutions, small insertions and deletions. In addition, genomic rearrangements, such as large deletions and duplications not detectable by PCR and Sanger sequencing, have been identified in a significant proportion of HNPCC families, which do not carry a pathogenic MMR gene point mutation. To clarify whether genomic rearrangements in MLH1, MSH2 or MSH6 also occur in patients carrying a point mutation, we subjected normal tissue DNA of 137 colorectal cancer (CRC) patients to multiplex ligation-dependent probe amplification (MLPA) analysis. Patients fulfilled the following pre-requisites: all patients met at least one criterion of the Bethesda guidelines and their tumors exhibited high microsatellite instability (MSI-H) and/or showed loss of expression of MLH1, MSH2 or MSH6 proteins. PCR amplification and Sanger sequencing of all exons of at least one MMR gene, whose protein expression had been lost in the tumor tissue, identified 52 index patients without a point mutation (Group 1), 71 index patients with a pathogenic point mutation in MLH1 (n=38) or MSH2 (n=22) or MSH6 (n=11) (Group 2) and 14 patients with an unclassified variant in MLH1 (n=9) or MSH2 (n=3) or MSH6 (n=2) (Group 3). In 13 of 52 patients of group 1 deletions of at least one exon were identified. In addition, in group 3 one EX1_15del in MLH1 was found. No genomic rearrangement was identified in group 2 patients. Genomic rearrangements represent a significant proportion of pathogenic mutations of MMR genes in HNPCC patients. However, genomic rearrangements are rare in patients carrying point mutations in MMR genes. These findings suggest the use of genomic rearrangement tests in addition to Sanger sequencing in HNPCC patients.

Authors+Show Affiliations

Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. stteffen.pistorius@uniklinikum-dresden.deNo 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
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16837128

Citation

Pistorius, Steffen, et al. "Genomic Rearrangements in MSH2, MLH1 or MSH6 Are Rare in HNPCC Patients Carrying Point Mutations." Cancer Letters, vol. 248, no. 1, 2007, pp. 89-95.
Pistorius S, Görgens H, Plaschke J, et al. Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations. Cancer Lett. 2007;248(1):89-95.
Pistorius, S., Görgens, H., Plaschke, J., Hoehl, R., Krüger, S., Engel, C., Saeger, H. D., & Schackert, H. K. (2007). Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations. Cancer Letters, 248(1), 89-95.
Pistorius S, et al. Genomic Rearrangements in MSH2, MLH1 or MSH6 Are Rare in HNPCC Patients Carrying Point Mutations. Cancer Lett. 2007 Apr 8;248(1):89-95. PubMed PMID: 16837128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genomic rearrangements in MSH2, MLH1 or MSH6 are rare in HNPCC patients carrying point mutations. AU - Pistorius,Steffen, AU - Görgens,Heike, AU - Plaschke,Jens, AU - Hoehl,Ruth, AU - Krüger,Stefan, AU - Engel,Christoph, AU - Saeger,Hans-Detlev, AU - Schackert,Hans K, Y1 - 2006/07/11/ PY - 2006/04/03/received PY - 2006/05/30/revised PY - 2006/06/07/accepted PY - 2006/7/14/pubmed PY - 2007/5/5/medline PY - 2006/7/14/entrez SP - 89 EP - 95 JF - Cancer letters JO - Cancer Lett VL - 248 IS - 1 N2 - Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease with high penetrance, caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 and MLH3. Most reported pathogenic mutations are point mutations, comprising single base substitutions, small insertions and deletions. In addition, genomic rearrangements, such as large deletions and duplications not detectable by PCR and Sanger sequencing, have been identified in a significant proportion of HNPCC families, which do not carry a pathogenic MMR gene point mutation. To clarify whether genomic rearrangements in MLH1, MSH2 or MSH6 also occur in patients carrying a point mutation, we subjected normal tissue DNA of 137 colorectal cancer (CRC) patients to multiplex ligation-dependent probe amplification (MLPA) analysis. Patients fulfilled the following pre-requisites: all patients met at least one criterion of the Bethesda guidelines and their tumors exhibited high microsatellite instability (MSI-H) and/or showed loss of expression of MLH1, MSH2 or MSH6 proteins. PCR amplification and Sanger sequencing of all exons of at least one MMR gene, whose protein expression had been lost in the tumor tissue, identified 52 index patients without a point mutation (Group 1), 71 index patients with a pathogenic point mutation in MLH1 (n=38) or MSH2 (n=22) or MSH6 (n=11) (Group 2) and 14 patients with an unclassified variant in MLH1 (n=9) or MSH2 (n=3) or MSH6 (n=2) (Group 3). In 13 of 52 patients of group 1 deletions of at least one exon were identified. In addition, in group 3 one EX1_15del in MLH1 was found. No genomic rearrangement was identified in group 2 patients. Genomic rearrangements represent a significant proportion of pathogenic mutations of MMR genes in HNPCC patients. However, genomic rearrangements are rare in patients carrying point mutations in MMR genes. These findings suggest the use of genomic rearrangement tests in addition to Sanger sequencing in HNPCC patients. SN - 0304-3835 UR - https://www.unboundmedicine.com/medline/citation/16837128/Genomic_rearrangements_in_MSH2_MLH1_or_MSH6_are_rare_in_HNPCC_patients_carrying_point_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(06)00407-1 DB - PRIME DP - Unbound Medicine ER -