High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families

Authors

  • A.J. Brea-Fernández,

    1. Grupo de Medicina Xenómica-USC, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
    2. Unidad de Investigación, Hospital General Universitario, Alicante, Spain
    Search for more papers by this author
  • J.M. Cameselle-Teijeiro,

    1. Servicio de Anatomía Patológica, Hospital Clínico Universitario, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain
    Search for more papers by this author
  • C. Alenda,

    1. Servicio de Anatomía Patológica, Hospital General Universitario, Alicante, Spain
    Search for more papers by this author
  • C. Fernández-Rozadilla,

    1. Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
    Search for more papers by this author
  • J. Cubiella,

    1. Servicio de Gastroenterología, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
    Search for more papers by this author
  • J. Clofent,

    1. Sección Aparato Digestivo, Servicio de Medicina Interna, Hospital de Sagunto, Sagunto, Spain
    2. Servicio de Gastroenterología, Complexo Hospitalario Universitario de Vigo, Spain
    Search for more papers by this author
  • J.M. Reñé,

    1. Servicio de Gastroenterología, Hospital Arnau de Vilanova, Lleida, Spain
    Search for more papers by this author
  • U. Anido,

    1. Servicio de Oncología Clínica, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
    Search for more papers by this author
  • M. Milá,

    1. Servicio de Bioquímica y Genética Molecular, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
    Search for more papers by this author
  • F. Balaguer,

    1. Servicio de Gastroenterología, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universitat de Barcelona, Barcelona, Spain
    Search for more papers by this author
  • A. Castells,

    1. Servicio de Gastroenterología, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universitat de Barcelona, Barcelona, Spain
    Search for more papers by this author
  • S. Castellvi-Bel,

    1. Servicio de Gastroenterología, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universitat de Barcelona, Barcelona, Spain
    Search for more papers by this author
  • R. Jover,

    1. Unidad de Investigación, Hospital General Universitario, Alicante, Spain
    Search for more papers by this author
  • A. Carracedo,

    1. Grupo de Medicina Xenómica-USC, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
    2. Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
    Search for more papers by this author
  • C. Ruiz-Ponte

    Corresponding author
    1. Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
    • Corresponding author: Clara Ruiz-Ponte, PhD, Fundacion Publica Galega de Medicina Xenomica (FPGMX), Hospital Clínico Universitario, Choupana s/n, 15706 Santiago de Compostela, Spain.

      Tel.: +34 981955195;

      fax: +34 981951473;

      e-mail: clara.ruiz.ponte@usc.es

    Search for more papers by this author

  • All the authors declare that there are no conflicts of interest.

Abstract

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2.

Ancillary