Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma

Casuscelli, Jozefina; Becerra, Maria F.; Manley, Brandon; Zabor, Emily C.; Reznik, Ed; Redzematovic, Almedina; Arcila, Maria E.; Tennenbaum, Daniel M.; Ghanaat, Mazyar; Kashan, Mahyar; Stief, Christian G.; Carlo, Maria I.; Voss, Martin H.; Feldman, Darren R.; Motzer, Robert J.; Chen, Yingbei; Reuter, Victor E.; Coleman, Jonathan; Russo, Paul; Hsieh, James J.; Hakimi, A. Ari

doi:10.1016/j.euf.2017.09.008

Cited by 41 publications

(33 citation statements)

References 30 publications

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“…No driver mutations were found in TERT, which is associated with aggressive disease (24). Similarly, BAP1, which causes aggressive ccRCC (25)(26)(27)(28), was mutated in only 2 samples, and neither sample was a primary tumor or PM (1 adrenal, 1 colon metastasis) (Supplemental Table 5).…”

Section: Resultsmentioning

confidence: 99%

Pancreatic tropism of metastatic renal cell carcinoma

Singla¹,

Xie²,

Zhang³

et al. 2020

JCI Insight

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Section: Resultsmentioning

confidence: 99%

Pancreatic tropism of metastatic renal cell carcinoma

Singla¹,

Xie²,

Zhang³

et al. 2020

JCI Insight

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“…Interestingly, 9 of the 20 mutations of SETD2 involved a hotspot frameshift mutation (K2fs). Recurrent mutations of TERT were identified in 9 samples (18%), including 6 C228T hotspot mutations and 2 C250T hotspot mutations, both located in the TERT promoter 7,8 . Additional mutations found in >10% of samples involved MTOR pathway members PTEN (7/50, 14%) and TSC2 (6/50, 12%), as well as Hippo pathway members NF2 (5/50, 10%) and FAT1 (5/50, 10%).…”

Section: Resultsmentioning

confidence: 99%

Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers

Malouf

Flippot

Dong

et al. 2020

Sci Rep

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Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRcc using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target. Sarcomatoid dedifferentiation has been reported in ~5% of clear-cell renal cell carcinomas (ccRCC) and is considered one of the most aggressive features of the disease 1. Sarcomatoid ccRCCs (sRCC) have been associated with high tumour burden and frequent metastatic dissemination, with a synchronous metastasis rate at diagnosis of 70%, compared to 30% in non-sRCCs 2. Patient prognosis is dismal, with median overall survival duration less than 12 months in patients treated with targeted molecular therapies 3. The mechanism underlying sarcomatoid dedifferentiation in ccRCC remains poorly defined. Several recent studies tried to define the genomic landscape of these tumours, with discordant results. Molecular profiling of

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“…The frequency of TERT alteration in mRCC is less than 10%, but recent series suggest that mutations in the TERT promoter may confer a poor prognosis. 15 16 Specifically, Casuscelli et al examined a series of 281 patients with both clear cell and non-clear cell RCC—the presence of TERT promoter mutations was associated with a HR of 2.68 (95%CI 1.19 to 6.01; p=0.013) for cancer-specific survival. From a biological perspective, TERT promoter mutations may be associated with upregulation of ETS-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis

Dizman

Lyou

Salgia

et al. 2020

J Immunother Cancer

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BackgroundThe clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) and IO.MethodsConsecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.Results91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of TERT. TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. While PBRM1 mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.ConclusionsOur analysis found that TERT promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with PBRM1 loss-of-function mutations.

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Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma

Abstract: 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.

Cited by 41 publications

References 30 publications

Pancreatic tropism of metastatic renal cell carcinoma

Pancreatic tropism of metastatic renal cell carcinoma

Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers

Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis

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