Founder effect of a pathogenic MSH2 mutation identified in Spanish families with Lynch syndrome

Authors

  • M Menéndez,

    1. Laboratori de Recerca Translacional, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
    • *

      Mireia Menéndez and Sergi Castellví-Bel were equal contributors to this article.

  • S Castellví-Bel,

    1. Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
    Search for more papers by this author
    • *

      Mireia Menéndez and Sergi Castellví-Bel were equal contributors to this article.

  • M Pineda,

    1. Laboratori de Recerca Translacional, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • R De Cid,

    1. CEA, Institut de Genomique, Centre National de Genotypage, Evry, France
    Search for more papers by this author
  • J Muñoz,

    1. Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
    Search for more papers by this author
  • S González,

    1. Laboratori de Recerca Translacional, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • À Teulé,

    1. Programa de Consell Genètic en Càncer, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • F Balaguer,

    1. Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
    Search for more papers by this author
  • T Ramón y Cajal,

    1. Servei d’Oncologia Mèdica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    Search for more papers by this author
  • Josep M. Reñé,

    1. Department of Gastroenterology, Hospital Universitari Arnau de Vilanova, Lleida, Spain.
    Search for more papers by this author
  • I Blanco,

    1. Programa de Consell Genètic en Càncer, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author
  • A Castells,

    1. Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
    Search for more papers by this author
  • G Capellà

    Corresponding author
    1. Laboratori de Recerca Translacional, Institut Català d’Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
    Search for more papers by this author

Gabriel Capellá, MD PhD
Laboratori de Recerca Translacioanal
Institut Català d’Oncologia, IDIBELL
Hospital Duran i Reynals,
Av. Gran Via 199-203
08907 L’Hospitalet de Llobregat, Barcelona, Spain.
Tel.: +34 93 260 7952;
fax: +34 93 260 7466;
e-mail: gcapella@iconcologia.net

Abstract

Menéndez M, Castellví-Bel S, Pineda M, de Cid R, Muñoz J, González S, TeuléÀ, Balaguer F, Ramón y Cajal T, Maria Reñé J, Blanco I, Castells A, Capellà G. Founder effect of a pathogenic MSH2 mutation identified in Spanish families with Lynch syndrome.

Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. The novel MSH2 c.[2635-3T>C; 2635-5C>T] mutation was identified in 4 Lynch families, cosegregating with the disease. This mutation, located in intron 15, was predicted to alter the correct mRNA processing by in silico analysis.

Our aim was to perform the c.[2635-3T>C; 2635-5C>T] mutation screening in high risk CRC cases and control populations, to evaluate the founder effect in our population by haplotype analysis and to confirm the pathogenic effect of the mutation by MSH2 expression studies.

Mutation screening was performed by SSCP and CSCE in genomic DNA from 323 high risk CRC cases and 289 controls. Haplotyping was performed analysing 4 MSH2 extragenic microsatellite markers (D2S288, D2S2227, D2S1247 and D2S1248) in 50 controls and mutation carriers by using the PHASE program. We analysed the effect of the mutation in mRNA processing by RT-PCR and in MSH2 expression by qRT-PCR using RNA from 5 mutation carriers and 18 controls.

None of the remaining high risk CRC cases or controls analysed harboured the mutation. We identified a common telomeric haplotype and two centromeric haplotypes, both rare in our population. Although we were not able to identify any abnormal transcript by RT-PCR with the design used, we observed a significant reduction of mRNA MSH2 expression in carriers when compared with controls.

Haplotype analyses suggest a founder effect of the c.[2635-3T>C; 2635-5C>T] MSH2 mutation and expression studies support a pathogenic role of this mutation.

Ancillary