A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred

Anja Wagner, Heleen Van Der Klift, Patrick Franken, Juul Wijnen, Cor Breukel, Vladimir Bezrookove, Ron Smits, Yulia Kinarsky, Alicia Barrows, Barbara Franklin, Jane Lynch, Henry T. Lynch, Riccardo Fodde

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Genomic deletions of the MSH2 gene are a frequent cause of hereditary nonpolyposis colorectal cancer (HNPCC), a common hereditary predisposition to the development of tumors in several organs including the gastrointestinal and urinary tracts and endometrium. The mutation spectrum at the MSH2 gene is extremely heterogeneous because it includes nonsense and missense point mutations, small insertions and deletions leading to frameshifts, and larger genomic deletions, the latter representing approximately 25% of the total mutation burden. Here, we report the identification and molecular characterization of the first paracentric inversion of the MSH2 locus known to cause HNPCC. Southern blot analysis and inverse PCR showed that the centromeric and telomeric breakpoints of the paracentric inversion map within intron 7 and to a contig 10 Mb 3′ of MSH2, respectively. Pathogenicity of the paracentric inversion was demonstrated by conversion analysis. The patient's lymphocytes were employed to generate somatic cell hybrids to analyze the expression of the inverted MSH2 allele in an Msh2-deficient rodent cellular background. The inversion was shown to abolish MSH2 expression by both northern and western analysis. This study confirms that Southern blot analysis still represents a useful and informative tool to screen for and identify complex genomic rearrangements in HNPCC. Moreover, monoallelic expression analysis represents an attractive approach to demonstrate pathogenicity of unusual mutations in autosomal dominant hereditary conditions.

Original languageEnglish
Pages (from-to)49-57
Number of pages9
JournalGenes Chromosomes and Cancer
Volume35
Issue number1
DOIs
StatePublished - 2002

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Hereditary Nonpolyposis Colorectal Neoplasms
Southern Blotting
Mutation
Virulence
Hybrid Cells
Gene Deletion
Missense Mutation
Endometrium
Urinary Tract
Point Mutation
Introns
Gastrointestinal Tract
Rodentia
Alleles
Lymphocytes
Polymerase Chain Reaction
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Genetics

Cite this

A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. / Wagner, Anja; Van Der Klift, Heleen; Franken, Patrick; Wijnen, Juul; Breukel, Cor; Bezrookove, Vladimir; Smits, Ron; Kinarsky, Yulia; Barrows, Alicia; Franklin, Barbara; Lynch, Jane; Lynch, Henry T.; Fodde, Riccardo.

In: Genes Chromosomes and Cancer, Vol. 35, No. 1, 2002, p. 49-57.

Research output: Contribution to journalArticle

Wagner, A, Van Der Klift, H, Franken, P, Wijnen, J, Breukel, C, Bezrookove, V, Smits, R, Kinarsky, Y, Barrows, A, Franklin, B, Lynch, J, Lynch, HT & Fodde, R 2002, 'A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred', Genes Chromosomes and Cancer, vol. 35, no. 1, pp. 49-57. https://doi.org/10.1002/gcc.10094
Wagner, Anja ; Van Der Klift, Heleen ; Franken, Patrick ; Wijnen, Juul ; Breukel, Cor ; Bezrookove, Vladimir ; Smits, Ron ; Kinarsky, Yulia ; Barrows, Alicia ; Franklin, Barbara ; Lynch, Jane ; Lynch, Henry T. ; Fodde, Riccardo. / A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. In: Genes Chromosomes and Cancer. 2002 ; Vol. 35, No. 1. pp. 49-57.
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