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Article
Nature Genetics  6, 273 - 281 (1994)
doi:10.1038/ng0394-273

Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation

Darryl Shibata1, Miguel Angel Peinado2, 3, Yurij lonov2, Sergei Malkhosyan2 & Manuel Perucho2

  1Department of Pathology, University of Southern California School of Medicine, Los Angeles, California 90033, USA

  2California Institute of Biological Research, 11099 North Torrey Pines Road, La Jolla, California 92037, USA

  3Present address: Institut de Recerca Oncologica, Hospital Duran i Reynals, Autovia de Castelldefels, Km 2,7 Hospitalet, 08907 Barcelona, Spain

 Correspondence should be addressed to M.P.

Genomic instability at simple repeated sequences (SRS) is a landmark for some sporadic and hereditary cancers of the colon. We have identified several human tumour cell lines with up to 1,000−fold increases in mutation rates for endogenous microsatellite sequences, relative to normal cells or tumour cells without the mutator phenotype and show that they are very early events in tumorigenesis. Our in vivo and in vitro results show that the genomic instability persists after transformation and that microsatellite mutations accumulate as consecutive somatic slippage events of a single or a few repeated units. This mechanism may account for the repeat expansions in triplet hereditary diseases and the same defect in replication fidelity in non−polyposis colon cancer could also contribute to the non−mendelian anticipation in these diseases.

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