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Human Molecular Genetics Advance Access published online on November 24, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi021
© 2004 by Oxford University Press
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Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis

Hafid Alazzouzi 1, Enric Domingo 1, Sara González 2, Ignacio Blanco 3, Manel Armengol 1, Eloi Espín 1, Alberto Plaja 1, Simó Schwartz 1, Gabriel Capella 2, and Simó Schwartz Jr.1*

1 Molecular Oncology and Aging Research, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain
2 Translational Research Unit, Institut Català d'Oncologia, Av. Gran Via s/n Km, 2.7,08907 L'Hospitalet, Spain
3 Genetic Counseling Unit, Institut Català d'Oncologia, Av. Gran Via s/n Km 2.7, 08907 L'Hospitalet, Spain

* To whom correspondence should be addressed.
Simó Schwartz Jr., E-mail: sschwartz{at}vhebron.net


  Abstract

Microsatellite instability (MSI) characterizes tumors arising in patients from the Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC). HNPCC is an hereditary autosomal dominant disease caused by germline mutations in genes from the DNA mismatch repair system (MMR). In these tumors, the loss of MMR compromises the genome integrity, allowing the progresive 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 hMLH1 and hMSH2 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 bat 26 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 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.


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