title: Telomerase is frequently activated in tumors with microsatellite instability.
abstract: Telomeres are specialized structures at the ends of eukaryotic chromosomes that are required for the complete replication and stability of naturally occurring chromosome ends. Telomere stabilization is critical for the unlimited cellular proliferation that is necessary for tumor formation. While most tumors achieve telomere stabilization through activation of telomerase, a subset of tumors utilize a recombination-based mechanism termed Alternative Lengthening of Telomeres (ALT) to maintain chromosome termini. Tumors utilizing ALT for telomere preservation will likely be refractory to treatment with telomerase inhibitors. Furthermore, tumors carrying mutations that predispose a cell to utilize ALT may activate this pathway when challenged by telomerase inhibition. Mutation of the mismatch repair (MMR) pathway enhances telomerase independent survival in yeast, with the survivors using recombination-based pathways for telomere maintenance. One possibility is that mutation of the MMR pathways alleviates suppression of recombination, thereby abrogating the need for telomerase activation. If true, one might predict an increased frequency of tumors harboring MMR mutation to use ALT for telomere maintenance. Here we characterized tumors with and without MMR mutation for the presence of telomerase activity versus ALT. We found similarly frequent activation of telomerase in tumors with and without MMR mutation, suggesting that human tumors with MMR mutation may respond favorably to treatment with telomerase inhibitors.
authors.affiliation: Department of Surgical Oncology, Philadelphia, Pennsylvania, USA.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ibanez de Caceres
authors.forename: Natalya
authors.initials: N
authors.lastname: Frolova
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Varkonyi
authors.forename: Essel
authors.initials: E
authors.lastname: Dulaimi
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Dominique
authors.initials: D
authors.lastname: Broccoli
authors.forename: Paul
authors.initials: P
authors.lastname: Cairns
mesh_terms: D020137:Base Pair Mismatch / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D005260:Female; D006801:Humans; D018895:Microsatellite Repeats; D010051:Ovarian Neoplasms / Q000235:genetics*; D019098:Telomerase / Q000494:pharmacology*; D016615:Telomere / Q000378:metabolism*
chemical_list: D019098:Telomerase