Research Article

Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC)

  1. Heleen van der Klift1,
  2. Juul Wijnen1,
  3. Anja Wagner3,
  4. Paul Verkuilen1,
  5. Carli Tops1,
  6. Robyn Otway4,
  7. Maija Kohonen-Corish4,5,
  8. Hans Vasen6,
  9. Cristina Oliani7,
  10. Daniela Barana7,
  11. Pal Moller8,
  12. Celia DeLozier-Blanchet9,
  13. Pierre Hutter10,
  14. William Foulkes11,
  15. Henry Lynch12,
  16. John Burn13,†,
  17. Gabriela Möslein14,†,
  18. Riccardo Fodde2,*

Article first published online: 7 JUN 2005

DOI: 10.1002/gcc.20219

Issue

Genes, Chromosomes and Cancer

Genes, Chromosomes and Cancer

Volume 44, Issue 2, pages 123–138, October 2005

Additional Information

How to Cite

van der Klift, H., Wijnen, J., Wagner, A., Verkuilen, P., Tops, C., Otway, R., Kohonen-Corish, M., Vasen, H., Oliani, C., Barana, D., Moller, P., DeLozier-Blanchet, C., Hutter, P., Foulkes, W., Lynch, H., Burn, J., Möslein, G. and Fodde, R. (2005), Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosom. Cancer, 44: 123–138. doi: 10.1002/gcc.20219

Author Information

  1. 1

    Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

  2. 2

    Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

  3. 3

    Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

  4. 4

    John Curtin School of Medical Research, Canberra, Australia

  5. 5

    Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia

  6. 6

    Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, Netherlands

  7. 7

    Divisione Clinicizzata di Oncologia Medica, Azienda Ospedaliera e Università degli Studi di Verona, Italy

  8. 8

    Department of Cancer Genetics, the Norwegian Radium Hospital, Oslo, Norway

  9. 9

    Division of Medical Genetics, University of Geneva Medical School, Geneva, Switzerland

  10. 10

    Unit of Genetics, ICHV, Sion, Switzerland

  11. 11

    Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada

  12. 12

    Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska

  13. 13

    Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, United Kingdom

  14. 14

    Department of Surgery, Heinrich Heine University, Düsseldorf, Germany

  1. †

    J.B. and G.M. represent the CAPP consortium, several of whose members submitted samples for mutation detection as part of the search for carriers of HNPCC eligible to take part in a long-term chemoprevention study [www.capp2.com].

*Dept. of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands

  1. †

    J.B. and G.M. represent the CAPP consortium, several of whose members submitted samples for mutation detection as part of the search for carriers of HNPCC eligible to take part in a long-term chemoprevention study [www.capp2.com].

Publication History

  1. Issue published online: 2 AUG 2005
  2. Article first published online: 7 JUN 2005
  3. Manuscript Accepted: 19 APR 2005
  4. Manuscript Received: 25 FEB 2005

Funded by

  • Dutch Cancer Society (KWF/NKB)
  • Netherlands Organisation for Scientific Research (NWO)
  • Deutsche Krebshilfe, Verbundprojekt familiarer Darmkrebs
  • Center of Medical System Biology (CMSB), established by the Netherlands Genomics Initiative (NGI) and NWO

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Abstract

A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, MSH2, MLH1, MSH6, and PMS2, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty-nine of the 48 rearrangements were found in MSH2, 13 in MLH1, 2 in MSH6, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty-four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly Alu repeats, in agreement with the differential distribution of deletions between the MSH2 and MLH1 genes: the higher number and density of Alu repeats in MSH2 corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, MLH1, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including Alu repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease-causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of MSH2 (3 cases) and MSH6 (1 case), a 2-kb insertion in intron 7 of PMS2, and a small (459-bp) deletion in intron 13 of MLH1. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR-based tests for their detection in diagnostic laboratories. © 2005 Wiley-Liss, Inc.

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