Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

J J P Gille, F B L Hogervorst, G Pals, J Th Wijnen, R J van Schooten, C J Dommering, G A Meijer, M E Craanen, P M Nederlof, D de Jong, C J McElgunn, J P Schouten, F H Menko

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

Original languageEnglish
Pages (from-to)892-7
Number of pages6
JournalBritish Journal of Cancer
Volume87
Issue number8
DOIs
Publication statusPublished - 7 Oct 2002

Cite this

Gille, J J P ; Hogervorst, F B L ; Pals, G ; Wijnen, J Th ; van Schooten, R J ; Dommering, C J ; Meijer, G A ; Craanen, M E ; Nederlof, P M ; de Jong, D ; McElgunn, C J ; Schouten, J P ; Menko, F H. / Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. In: British Journal of Cancer. 2002 ; Vol. 87, No. 8. pp. 892-7.
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abstract = "Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4{\%}) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7{\%} harboured germline gene defects. Genomic deletions accounted for 54.8{\%} of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.",
keywords = "Adaptor Proteins, Signal Transducing, Base Pair Mismatch/genetics, Carrier Proteins, Cohort Studies, Colorectal Neoplasms/genetics, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, DNA Repair/genetics, DNA-Binding Proteins, Family, Female, Gene Deletion, Germ-Line Mutation, Humans, Male, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins/genetics, Nuclear Proteins, Pedigree, Polymerase Chain Reaction, Proto-Oncogene Proteins/genetics",
author = "Gille, {J J P} and Hogervorst, {F B L} and G Pals and Wijnen, {J Th} and {van Schooten}, {R J} and Dommering, {C J} and Meijer, {G A} and Craanen, {M E} and Nederlof, {P M} and {de Jong}, D and McElgunn, {C J} and Schouten, {J P} and Menko, {F H}",
note = "Copyright 2002 Cancer Research UK",
year = "2002",
month = "10",
day = "7",
doi = "10.1038/sj.bjc.6600565",
language = "English",
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Gille, JJP, Hogervorst, FBL, Pals, G, Wijnen, JT, van Schooten, RJ, Dommering, CJ, Meijer, GA, Craanen, ME, Nederlof, PM, de Jong, D, McElgunn, CJ, Schouten, JP & Menko, FH 2002, 'Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach' British Journal of Cancer, vol. 87, no. 8, pp. 892-7. https://doi.org/10.1038/sj.bjc.6600565

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. / Gille, J J P; Hogervorst, F B L; Pals, G; Wijnen, J Th; van Schooten, R J; Dommering, C J; Meijer, G A; Craanen, M E; Nederlof, P M; de Jong, D; McElgunn, C J; Schouten, J P; Menko, F H.

In: British Journal of Cancer, Vol. 87, No. 8, 07.10.2002, p. 892-7.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

AU - Gille, J J P

AU - Hogervorst, F B L

AU - Pals, G

AU - Wijnen, J Th

AU - van Schooten, R J

AU - Dommering, C J

AU - Meijer, G A

AU - Craanen, M E

AU - Nederlof, P M

AU - de Jong, D

AU - McElgunn, C J

AU - Schouten, J P

AU - Menko, F H

N1 - Copyright 2002 Cancer Research UK

PY - 2002/10/7

Y1 - 2002/10/7

N2 - Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

AB - Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

KW - Adaptor Proteins, Signal Transducing

KW - Base Pair Mismatch/genetics

KW - Carrier Proteins

KW - Cohort Studies

KW - Colorectal Neoplasms/genetics

KW - Colorectal Neoplasms, Hereditary Nonpolyposis/genetics

KW - DNA Repair/genetics

KW - DNA-Binding Proteins

KW - Family

KW - Female

KW - Gene Deletion

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - MutL Protein Homolog 1

KW - MutS Homolog 2 Protein

KW - Neoplasm Proteins/genetics

KW - Nuclear Proteins

KW - Pedigree

KW - Polymerase Chain Reaction

KW - Proto-Oncogene Proteins/genetics

U2 - 10.1038/sj.bjc.6600565

DO - 10.1038/sj.bjc.6600565

M3 - Article

VL - 87

SP - 892

EP - 897

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 8

ER -