The
telomerase reverse transcriptase (TERT) promoter, an important
element of
telomerase expression, has emerged as a target of
cancer-specific mutations. Originally described in
melanoma, the mutations in TERT promoter have been shown to be common in certain other
tumor types that include
glioblastoma,
hepatocellular carcinoma, and
bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated
tumors from a well-characterized series of 327 patients with urothelial cell
carcinoma of bladder. The somatic mutations, mainly at positions -124 and -146 bp from ATG start site that create binding motifs for E-twenty six/
ternary complex factors (Ets/TCF), affected 65.4% of the
tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and
tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1
tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in
bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.