Exact Sciences Corp, Phoenix, AZ
Aimee Jalkanen , Gargi D. Basu , David W. Hall , Jess R Hoag , Janine R. LoBello , Frederick L. Baehner , Snehal Govind Thakkar , Tanya B. Dorff
Background: Some of the most common mutations seen across cancers occur in TERT, where promoter mutations upregulate TERT transcription. In bladder cancer, TERT mutations are associated with poor prognosis, especially for recurrence. In this study, we identified TERT promoter mutations in bladder cancer and determined whether mutations at other genes were significantly associated. We also examined whether TERT mutation frequency is associated with age or gender. Methods: We utilized the Oncomap ExTra genomic profiling assay to identify alterations. This assay performs tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations. In addition to the exome, several noncoding regions are sequenced, including the TERT promoter. Single-nucleotide variants, indels, copy number alterations, alternative transcripts, and gene fusions are all detected. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also calculated. Results: Of 194 bladder cancer patient specimens assayed between April 2018 and August 2022, 153 (78.9%) carried a TERT promotor mutation (Table). The C228T and C250T single base substitutions were the most common, at 57.7% and 15.5%, respectively. Of note, one patient had a TERT fusion caused by an inversion involving MARCHF6 as the partner gene. Many patients harbored mutations in other genes, with two possibly associated with TERT status: BRCA2 was mutated in 6 (3.9%) TERT-mutated and 7 (17.1%) TERT-wild type patients (Fisher’s Exact Test, p=0.007), and FGFR3 was mutated in 33 (21.6%) TERT-mutated and 3 (7.3%) TERT-wild type patients (p=0.042). In addition, TMB-high was in 93 (60.8%) TERT-mutated and 10 (24.4%) TERT-wild type patients (p=0.071). None of these associations were significant after correcting for the false discovery rate. There was no significant difference in median (or average) age of individuals with versus without a TERT mutation (71.0 and 70.0 yrs, respectively). In addition, there was no significant difference in frequency of TERT alterations in males (82.0%) versus females (70.9%). Conclusions: The Oncomap ExTra assay allowed identification of both commonly observed and rare TERT promoter mutations, including a fusion, in 78.9% of bladder cancer patients. Such assays are useful to identify both TERT alterations prognostic for progression and patients eligible for clinical trials evaluating TERT-directed therapies. In addition, TERT mutations may be associated with FGFR3 mutations and high TMB, which have matched therapies, though these associations need to be validated in an independent cohort.
TERT alterations | Number (%) of patients |
---|---|
No TERT alteration | 41 (21.1%) |
Any TERT alteration | 153 (78.9%) |
Alteration: | |
C228T | 112 (57.7%) |
C250T | 30 (15.5%) |
C242T + C243T | 4 (2.1%) |
A161C | 3 (1.5%) |
G149T | 2 (1.0%) |
C288A | 1 (0.5%) |
MARCH6/TERT Fusion | 1 (0.5%) |
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