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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 Cancer. 2002 Sep; 35(1):49-57.GC

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.

Authors+Show Affiliations

MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

12203789

Citation

Wagner, Anja, et al. "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 & Cancer, vol. 35, no. 1, 2002, pp. 49-57.
Wagner A, van der Klift H, Franken P, et al. 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 Cancer. 2002;35(1):49-57.
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, H., & 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 & Cancer, 35(1), 49-57.
Wagner A, et al. 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 Cancer. 2002;35(1):49-57. PubMed PMID: 12203789.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. AU - Wagner,Anja, AU - van der Klift,Heleen, AU - Franken,Patrick, AU - Wijnen,Juul, AU - Breukel,Cor, AU - Bezrookove,Vladimir, AU - Smits,Ron, AU - Kinarsky,Yulia, AU - Barrows,Alicia, AU - Franklin,Barbara, AU - Lynch,Jane, AU - Lynch,Henry, AU - Fodde,Riccardo, PY - 2002/8/31/pubmed PY - 2002/12/4/medline PY - 2002/8/31/entrez SP - 49 EP - 57 JF - Genes, chromosomes & cancer JO - Genes Chromosomes Cancer VL - 35 IS - 1 N2 - 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. SN - 1045-2257 UR - https://www.unboundmedicine.com/medline/citation/12203789/A_10_Mb_paracentric_inversion_of_chromosome_arm_2p_inactivates_MSH2_and_is_responsible_for_hereditary_nonpolyposis_colorectal_cancer_in_a_North_American_kindred_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1045-2257&date=2002&volume=35&issue=1&spage=49 DB - PRIME DP - Unbound Medicine ER -