1. ¹Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK
2. ²Institute of Forensic Medicine, University of Oslo, Rikshospitalet, University Hospital, Oslo 0027, Norway
3. ³Department of Pathology, University of Leicester, Robert Kilpatrick Building, PO Box 65, Leicester Royal Infirmary, Leicester LE2 7LX, UK

Correspondence: NJ Royle, E-mail: njr@le.ac.uk

⁴Current address: Cancer Research UK, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK

⁵Current address: Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK

⁶Current address: Department of Surgery, Akershus University Hospital, University of Oslo, Nordbyhagen N-1474, Norway

Received 11 September 2003; Revised 9 December 2003; Accepted 5 January 2004; Published online 29 March 2004.

Abstract

Human telomeres are essential for genome stability and are composed of long simple tandem repeat arrays (STRs), comprising the consensus TTAGGG repeat interspersed, at the proximal end, with sequence–variant repeats. While the dynamics of telomere attrition through incomplete replication has been studied extensively, the effects on telomeres of error-prone DNA repair processes, known to affect other STRs, are poorly understood. We have compared the TTAGGG and sequence–variant interspersion patterns in the proximal 720 bp of telomeres in colon cancer and normal DNA samples. The frequency of telomere mutations was 5.8% per allele in a randomly collected panel of sporadic colon cancers, showing that telomere mutations occur in vivo. The mutation frequency rose to 18.6% per allele in sporadic tumours that exhibit instability at the polyA tract in the TGFRII gene and to 35% per allele in tumours with somatic mutations in the hMSH2 gene. The majority of the characterized mutations resulted in the loss of one or a few repeats. If the mutation spectrum and frequency described here is reiterated in the rest of the array, there is the potential for extensive telomere destabilization especially in mismatch repair-defective cells. This may in turn lead to a greater requirement for telomere length maintenance earlier in tumourigenesis.