E314: Telomerase reverse transcriptase (TERT) promoter mutations are associated with higher tumor mutational burden and UV mutational signature in melanoma

TERT promoter mutations (TERTp-mut) are highly prevalent in melanoma and historically associated with poor prognosis, but recently identified as a predictor of response to BRAF/MEK inhibition. In addition to its role in maintaining telomere length, TERT regulates NF-κB and AKT signaling and inhibits apoptosis, which may enable cells to survive despite mutational stress. This study examines TERTp-mut in the context of immune checkpoint inhibition (ICI) and favorable genomic factors in melanoma: tumor mutational burden (TMB) and UV mutational signature.

Methods:

We interrogated an institutional clinical tumor sequencing database for TERTp-mut, TMB, and overall survival (OS) in melanoma and other solid tumors. Single base substitution signature analysis was performed on raw sequencing data using tempoSig R package.

Results:

TERTp-mut were more common in cutaneous (76% n=1267) than acral (7% n=134), ocular (< 1% n=732), or anogenital mucosal (2% n=101) melanoma; it occurred in 75-80% of BRAF-, NRAS-, or NF1-mutant melanomas, but only 14% of melanomas without these drivers. TERTp-mut was associated with significantly increased TMB and a UV mutational signature. In the entire melanoma cohort, longer OS was seen in TERTp-mut patients compared to TERT promoter wildtype (TERTp-WT), possibly representing the better outcomes of cutaneous melanoma versus acral, ocular and mucosal subtypes. Among cutaneous melanomas, OS did not differ based on TERTp status, both among patients who did and did not receive ICI. In addition to melanoma, we identified four other solid tumor types with high prevalence of TERTp-mut in the database: urothelial (65% n=3863), hepatocellular (55% n=418), thyroid (52% n=1211), and head/neck squamous cell (37% n=548) cancers. In all tumor types TERTp-mut was associated with significantly higher TMB, but not associated with improved OS.

Conclusions:

TERTp-mut are highly prevalent across multiple solid tumors and consistently associated with higher TMB. UV-associated mutations are more prominent in TERTp-mut than TERTp-WT melanoma. Despite these favorable mutational profiles, TERTp-mut was not associated with improved OS in cutaneous melanoma or any of the other cancers we examined. This study is limited by potential bias of sequencing database specimens, which are enriched for advanced and metastatic disease. Future work will focus on mechanisms by which TERTp-mut may enable increased TMB and tissue- and exposure-specific mutations, and by which TERTp-mut may influence treatment efficacy.