Prognostic value of TERT alterations, mutational and copy number alterations burden in urothelial carcinoma Journal Article
| Authors: | Isharwal, S.; Audenet, F.; Drill, E.; Pietzak, E. J.; Iyer, G.; Ostrovnaya, I.; Cha, E.; Donahue, T.; Arcila, M.; Jayakumaran, G.; Berger, M. F.; Rosenberg, J. E.; Bajorin, D. F.; Coleman, J.; Dalbagni, G.; Reuter, V. E.; Bochner, B. H.; Solit, D. B.; Al-Ahmadie, H. A. |
| Article Title: | Prognostic value of TERT alterations, mutational and copy number alterations burden in urothelial carcinoma |
| Abstract: | The majority of TERT mutations are located at two promoter region hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden/Mb had a more favorable outcome compared to tumors with a low mutational burden/Mb. © 2017 European Association of Urology Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C > T and 1 295 250 C > T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p = 0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p < 0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46–3.65; p < 0.001; and HR 0.96, 95% CI 0.93–0.99; p = 0.002), disease-specific survival (HR 2.23, 95% CI 1.41–3.53; p < 0.001; and HR 0.96, 95% CI 0.93–0.99; p = 0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05–2.53; p = 0.029; and HR 0.98, 95% CI 0.96–1.00; p = 0.063) in multivariate models. Patient summary: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden. © 2017 European Association of Urology |
| Keywords: | adult; controlled study; treatment outcome; aged; middle aged; human cell; major clinical study; overall survival; promoter region; tumor volume; cohort analysis; genetic association; bladder tumor; telomerase reverse transcriptase; urogenital tract tumor; point mutation; transitional cell carcinoma; disease specific survival; pik3ca gene; ptprd gene; copy number variation; chromosome 5; cdkn2a gene; oncological parameters; cdkn1a gene; rb1 gene; erbb2 gene; arid1a gene; metastasis free survival; disease burden; tert gene; human; article; prognostic assessment; ercc2 gene; tsc1 gene; cdkn2b gene |
| Journal Title: | European Urology Focus |
| Volume: | 5 |
| Issue: | 2 |
| ISSN: | 2405-4569 |
| Publisher: | Elsevier B.V. |
| Date Published: | 2019-03-01 |
| Start Page: | 201 |
| End Page: | 204 |
| Language: | English |
| DOI: | 10.1016/j.euf.2017.07.004 |
| PUBMED: | 28802642 |
| PROVIDER: | scopus |
| PMCID: | PMC5809230 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
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