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Sources of Funding: Ruth L. Kirschstein National Research Service Award T32CA082088, Marie-Josee and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748

Introduction

Telomerase reverse transcriptase (TERT) is the most frequently altered gene in urothelial cancer (UC), detected across all grades and stages of disease. We sought to characterize TERT alterations within a prospective cohort of UC treated at our institute and compare the frequency of genomic alterations in TERT promoter mutant vs wild-type UC specimens.

Methods

Patients diagnosed with bladder urothelial tumors were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed for somatic point mutations, truncations, copy number alterations, and insertions/deletions using the MSK-IMPACT NGS assay that detects alterations in all exons and select introns of 410 oncogenes and tumor suppressor genes as well as the entire TERT promoter region.

Results

329 UC were sequenced of which 236 (71.7%) harbored TERT mutations, the majority being promoter region hotspots (chr5: 1295228 G>A [81%] and chr5:1295250 G>A [16%]). Patients with TERT promoter mutations were significantly older than those without (69.01 ± 10.70 years vs. 65.44 ± 11.78 years, p=0.0317). UC with TERT promoter mutations had significantly higher mutation count [median 10 (range: 2-76) vs median 5 (range: 0-119)] as well as copy number alterations [median 0.11 (range: 0-0.68) vs median 0.047 (range: 0-0.65)]. In non-invasive UC, TERT promoter mutations were identified in 14 of 23 low grade (61%) and in 26 of 30 high grade (87%) tumors. Between UC with and without TERT promoter mutations, there was a very significant difference in mutation frequencies of ARID1A(34% vs 11%), PIK3CA(27% vs 13%), FGFR3(33% vs 16%), CREBBP(19% vs 4%), CDKN1A(17% vs 2%), ERBB2(26% vs 9%), ERCC2(15% vs 3%), TSC1(11% vs 0%), KMT2C(17% vs 9%) (all with p < 0.005).

Conclusions

TERT is the most frequently altered gene in bladder cancer with the majority of TERT alterations comprised of two hotspot mutations. UC with TERT promoter mutations tends to occur in older patients and is associated with overall higher mutation count and copy number alterations. A number of genes are differentially mutated in UC with and without TERT promoter mutations and may suggest a link between TERT promoter mutations and distinct mutations profiles in UC.

Funding

Ruth L. Kirschstein National Research Service Award T32CA082088, Marie-Josee and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant No. P30-CA008748