{
  "abstract": "Background The most prevalent somatic mutations in melanoma are in the telomerase reverse transcriptase (TERT) promoter. Historically, TERT promoter mutations have been regarded as predictors of poor outcomes. Recent data suggest that different TERT promoter mutations have disparate impacts on prognosis. We sought to identify the prognostic significance of different mutational loci in the TERT promoter in the context of modern therapy, specifically in advanced and metastatic melanoma.Methods Using a clinical sequencing database, we identified characteristics associated with TERT promoter mutations in melanoma and other solid tumors. We compared tumor mutational burden and UV mutational signatures in TERT-mutant vs. TERT-wildtype tumors. We performed univariable and multivariable survival analysis using known prognostic features and common TERT promoter mutations.Results TERT promoter mutations are highly prevalent in cutaneous melanoma (76%), urothelial carcinoma (67%), hepatocellular carcinoma (54%), head and neck squamous cell carcinoma (37%), and thyroid cancer (52%), but the distribution of mutations differs across these diseases. Tumor mutational burden is significantly higher in TERT-mutant tumors across all tumor types, and UV mutational signature is significantly higher in TERT-mutant tumors in sun-exposed areas (cutaneous melanoma and head and neck squamous cell carcinoma) ( figure 1). The C250T TERT promoter mutation (39% of TERT promoter mutations in cutaneous melanoma) was associated with worse overall survival compared with other TERT promoter mutations, including the other common mutations (C228T, 46% of TERT promoter mutations; and CC242-243TT, 7% of TERT promoter mutations in cutaneous melanoma), in the MSK-IMPACT cutaneous melanoma cohort, and specifically in patients with metastatic disease (figure 2).Conclusions TERT promoter mutational status, specifically C250T mutations, have prognostic value in metastatic cutaneous melanoma. Paradoxically, while TERT promoter mutations are associated with increased tumor mutational burden and UV mutational signature, both of which predict response to immune checkpoint inhibition, C250T mutations are associated with worse outcomes. Further study should focus on the mechanisms of oncogenesis, tumor progression, and immune evasion related to TERT.Abstract 139 Figure 1TERT promoter mutations are associated with tumor mutational burden and UV mutagenesis in sun-exposed tumors. (A) Comparison of tumor mutational burden (within tumor type) in TERT-wildtype vs. TERT-mutant tumors, median with interquartile range. (B) Comparison of UV mutational signature (SBS7) in TERT-wildtype vs. TERT-mutant tumors. UV, ultraviolet; HCC, hepatocellular carcinoma; HNCSS, head and neck squamous cell carcinoma; SBS7, single base substitution signature 7Abstract 139 Figure 2TERT promoter C250T mutations are associated with worse overall survival in metastatic cutaneous melanoma. Overall survival in the entire MSK-IMPACT cutaneous melanoma cohort, limited to metastatic disease only and stratified by common TERT promoter mutations",
  "authors": [
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Joshua C Leinwand"
    },
    {
      "affiliations": [
        "University of Pittsburgh Medical Center, Pittsburgh, PA, USA"
      ],
      "name": "Elizabeth S Koh"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Edmund Bartlett"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Danielle Bello"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Mary Brady"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "James J Harding"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Luc Morris"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Charlotte E Ariyan"
    }
  ],
  "title": "139 TERT promoter C250T mutations are associated with worse overall survival in metastatic cutaneous melanoma",
  "uid": "65627533-e51a-5587-b46b-774f4260ebf1"
}