Molecular Characteristics of Advanced Clear Cell Renal Cell Carcinoma (ccRCC) Harboring TERT Mutations

ASCO Genitourinary Cancers Symposium 2023 PRESENTATION
Authors Nataliya Mar, Ellen B. Jaeger, Arya Ashok, Arash Rezazadeh

Background: There is a large unmet need for identifying prognostic and predictive biomarkers in advanced RCC. TERT is a catalytic subunit of the telomerase enzyme and TERT promoter mutations lead to increased telomerase activity, which promotes tumorigenesis by preventing telomere shortening. Emerging data suggests a correlation between TERT promoter mutations (pTERTmut) and improved responses to immune checkpoint inhibitors in urothelial carcinoma (UC), while there is paucity of such data in RCC. This study aims to analyze the immune biomarker environment and co-mutational landscape in TERT mutated versus wild-type RCC.

Methods: A retrospective analysis of patients with advanced ccRCC who completed sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq) was performed. De-identified data was analyzed for presence of pTERTmut, all other TERT mutations (otherTERT), and TERT wildtype (wtTERT). Companion alterations and immune biomarkers were compared between these three groups.

Results: A total of 866 samples was analyzed, with 58% from primary renal lesions and 42% from a metastatic site. The frequency of all TERT mutations was 8.2% (71/866). pTERTmut was present in 5.6% (28/502) of primary and 5.5% (20/364) of metastatic sites, while otherTERT was present in 3.0% (15/502) of primary and 2.2% (8/364) of metastatic sites. Tumor mutational burden (TMB) was performed in 764 samples and only 0.4% had TMB greater than 10 m/MB, all of which were wtTERT. Median TMB was 2.08 m/MB across all samples, with 1.91 m/MB in pTERTmut, 1.72 m/MB in otherTERT, and 2.31 m/MB in wtTERT. Only 0.2% of 834 samples harbored MSI-high and 1.4% of 295 samples were mismatch repair deficient (dMMR), all of which were wtTERT. PD-L1 status was available in 439 samples, with 14% scored as positive (PD-L1+) with a combined positive score >10. Of PD-L1+, 4.8% was in pTERTmut, 3.2% in otherTERT, and 92.1% in wtTERT. Neoantigen tumor burden of all non-silent mutations was evaluated in 698 samples, with a median value of 2.11 in pTERTmut, 1.58 in otherTERT, and 2.11 in wtTERT. PBRM1 co-mutations were noted in 22.9% of samples with pTERTmut, 21.7% in otherTERT, and 33.2% in wtTERT. Additional RCC co-mutations are listed in the table. RCC mRNA and UC cohort data analysis is in progress.

Conclusions: This is the largest analysis of the molecular and immune landscape of TERT mutated ccRCC. Interestingly, this dataset showcases that traditional immune biomarkers (TMB, MSI, dMMR, and PD-L1) do not appear to be highly prevalent in RCC and their use in clinical practice may be limited. Further investigation into the TERT biomarker candidate is warranted.

Selected genomic co-mutations with TERT alterations and wtTERT.
Mutation pTERTmut otherTERT wtTERT
VHL 68.8% 73.9% 61.1%
SETD2 6.2% 17.4% 21.3%
BAP1 8.3% 8.7% 12.8%
TSC1 10.4% 4.3% 4.7%
MTOR 10.4% 4.3% 2.6%
TP53 12.5% 17.4% 7.8%
NTRK3 6.2% 17.4% 7.5%