title: Telomere instability detected in sporadic colon cancers, some showing mutations in a mismatch repair gene.
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 TGFbetaRII 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.
authors.affiliation: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
authors.forename: Hilda Amelia
authors.initials: HA
authors.lastname: Pickett
authors.forename: Duncan Martin
authors.initials: DM
authors.lastname: Baird
authors.forename: Per
authors.initials: P
authors.lastname: Hoff-Olsen
authors.forename: Gunn Iren
authors.initials: GI
authors.lastname: Meling
authors.forename: Torleiv Ole
authors.initials: TO
authors.lastname: Rognum
authors.forename: Jacqui
authors.initials: J
authors.lastname: Shaw
authors.forename: Kevin Paul
authors.initials: KP
authors.lastname: West
authors.forename: Nicola Jane
authors.initials: NJ
authors.lastname: Royle
mesh_terms: D020137:Base Pair Mismatch; D003110:Colonic Neoplasms / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016615:Telomere
chemical_list: D018125:Receptors, Transforming Growth Factor beta