Telomere instability detected in sporadic colon cancers, some showing mutations in a mismatch repair gene.
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.
Pickett
Hilda Amelia
HA
Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
Baird
Duncan Martin
DM
Hoff-Olsen
Per
P
Meling
Gunn Iren
GI
Rognum
Torleiv Ole
TO
Shaw
Jacqui
J
West
Kevin Paul
KP
Royle
Nicola Jane
NJ
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
D018125:Receptors, Transforming Growth Factor beta