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

• Published in: Genes chromosomes & cancer Vol. 35; no. 1; pp. 49 - 57
• Main Authors: 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, Fodde, Riccardo
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 01.09.2002
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - genetics; Adult; Aged; Animals; Blotting, Southern; Chromosome Inversion; Chromosomes, Human, Pair 2 - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - enzymology; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Cytogenetic Analysis; DNA-Binding Proteins; Female; Gene Expression Profiling; Gene Silencing; Humans; Hybrid Cells; In Situ Hybridization, Fluorescence; Male; Mice; Middle Aged; MutS Homolog 2 Protein; Pedigree; Polymerase Chain Reaction; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics
• ISSN: 1045-2257; 1098-2264
• DOI: 10.1002/gcc.10094

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. © 2002 Wiley‐Liss, Inc.