@article{ff4de1480ea0440782dfc48faf8f3587,
title = "Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma",
abstract = "Background: Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. Objective: To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non–clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. Design, setting, and participants: DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. Outcome measurements and statistical analysis: Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. Results and limitations: TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1–18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19–6.01; p = 0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. Conclusions: Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. Patient summary: We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non–clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.",
keywords = "Mortality, Prognosis, Renal cell carcinoma, Sequencing analysis, TERT promoter",
author = "Jozefina Casuscelli and Becerra, {Maria F.} and Manley, {Brandon J.} and Zabor, {Emily C.} and Ed Reznik and Almedina Redzematovic and Arcila, {Maria E.} and Tennenbaum, {Daniel M.} and Mazyar Ghanaat and Mahyar Kashan and Stief, {Christian G.} and Maria Carlo and Voss, {Martin H.} and Feldman, {Darren R.} and Motzer, {Robert J.} and Yingbei Chen and Reuter, {Victor E.} and Coleman, {Jonathan A.} and Paul Russo and Hsieh, {James J.} and Hakimi, {Abraham Ari}",
note = "Funding Information: Other: None. Financial disclosures: A. Ari Hakimi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Acknowledgments: Jozefina Casuscelli was sponsored by German Research Foundation grant CA1403/1-1 . Brandon J. Manley and Mazyar Ghanaat were supported by Ruth L. Kirschstein National Research Service Award T3to2CA082088. Brandon J. Manley, Jonathan A. Coleman, Mazyar Ghanaat, and A. Ari Hakimi were supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and NIH/NCI Cancer Center Support Grant P30 CA008748 . James J. Hsieh was supported by the Jill and Jeffrey Weiss Fund for the Cure of Kidney Cancer and the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund . Funding Information: Other: None. Financial disclosures: A. Ari Hakimi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. Acknowledgments: Jozefina Casuscelli was sponsored by German Research Foundation grant CA1403/1-1. Brandon J. Manley and Mazyar Ghanaat were supported by Ruth L. Kirschstein National Research Service Award T3to2CA082088. Brandon J. Manley, Jonathan A. Coleman, Mazyar Ghanaat, and A. Ari Hakimi were supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and NIH/NCI Cancer Center Support Grant P30 CA008748. James J. Hsieh was supported by the Jill and Jeffrey Weiss Fund for the Cure of Kidney Cancer and the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund. Publisher Copyright: {\textcopyright} 2017 European Association of Urology",
year = "2019",
month = jul,
doi = "10.1016/j.euf.2017.09.008",
language = "English",
volume = "5",
pages = "642--649",
journal = "European Urology Focus",
issn = "2405-4569",
number = "4",
}