Abstract 565: Telomerase reverse transcriptase promoter alterations in human bladder cancer

Abstract

Abstract The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of the enzyme telomerase, (aka telomere terminal transferase), which contains both protein and RNA subunits. TERT is a RNA-dependent polymerase which increases the length of telomeres at the ends of each chromosome by adding TTAGGG repeats. TERT polymerase uses RNA as a complementary primer to elongate telomeric G-rich repeat sequences in the 5’ to 3’ direction. TERT is essential and active in germ cells, stem cells, primary tumors, and immortalized cells and acts to maintain adequate telomeres. However, in somatic cells, TERT expression is reduced or absent and telomeres gradually shorten during the S phase of each cell cycle due to replication-dependent loss of telomere terminal sequences. Adequate telomere length is important for preserving genome stability, regulating cell replication, and preventing cell death. Somatic TERT promoter alterations were recently reported in melanoma, glioma, and in small sample sets from other cancers including bladder cancer. These are thought to drive re-expression of TERT in cancer cells. In this study, given recent reports of somatic TERT promoter alterations in bladder cancer, polymerase chain reaction and Sanger sequencing were performed to examine a region of the TERT promoter in 58 bladder tumors. The TERT promoter was altered in 90% of 58 tumors by 44 germline (21 unique, 20 novel) and 53 somatic variants (11 unique, 4 novel). Somatic alterations were observed in 67% of tumors. The majority of variants were C>T DNA changes, three variants occurred as both germline and somatic, and a subset of variants created or altered transcription factor binding sites and promoter CpGs. Analyses of telomere length showed significantly shorter telomeres in tumor tissue versus adjacent normal tissue from the same patient (p=0.004) indicating TERT may not sufficiently lengthen telomeres in rapidly proliferating cancer cells. Interestingly, somatic TERT promoter alterations were not associated with stage, grade, or alterations in other bladder cancer genes identified by exome sequencing. We speculate that TERT promoter alterations are frequent and early events in bladder cancer and identification of TERT alterations in urine may provide a biomarker for early diagnosis and monitoring of bladder cancer. Note: This abstract was not presented at the meeting. Citation Format: Sevilay Turan. Telomerase reverse transcriptase promoter alterations in human bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 565. doi:10.1158/1538-7445.AM2014-565