title: Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.
abstract: Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the genome integrity, allowing the progressive accumulation of mutations and the establishment of a mutator phenotype in a recessive manner. It is not clear, however, whether MSI can be detected in HNPCC carriers before tumor diagnosis. The aim of this study was to evaluate the presence of genetic instability in MMR gene carriers in peripheral blood lymphocytes of carriers and non-carriers members of two HNPCC families harboring a germline MLH1 and MSH2 mutation, respectively. An extensive analysis of the allelic distribution of single molecules of the polyA tract bat26 was performed using a highly sensitive PCR-cloning approach. In non-carriers, the allelic distribution of single bat26 molecules followed a gaussian distribution with no bat26 alleles shorter than (A)21. All mutation carriers showed unstable alleles [(A)20 or shorter] with an overall frequency of 5.6% (102/1814). We therefore suggest that low levels of genomic instability characterize MMR mutation carriers. These observations suggest that somatic mutations accumulate well before tumor diagnosis. Even though it is not clear whether this is due to the presence of a small percentage of cells with lost MMR or due to MMR haploinsufficiency, detection of these short unstable alleles might help in the identification of asymptomatic carriers belonging to families with no detectable MMR gene mutations.
authors.affiliation: Molecular Oncology and Aging Research, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Hafid
authors.initials: H
authors.lastname: Alazzouzi
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Sara
authors.initials: S
authors.lastname: González
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Manel
authors.initials: M
authors.lastname: Armengol
authors.forename: Eloi
authors.initials: E
authors.lastname: Espín
authors.forename: Alberto
authors.initials: A
authors.lastname: Plaja
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C092008:PRRC2A protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein