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

138 Citations (Scopus)


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
Issue number8
Publication statusPublished - 7 Oct 2002


  • Adaptor Proteins, Signal Transducing
  • Base Pair Mismatch/genetics
  • Carrier Proteins
  • Cohort Studies
  • Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
  • Colorectal Neoplasms/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

Cite this