Abstract 1434: Co-occurrence of alterations impacting telomere elongation

Abstract

Abstract Background: Tumor cells need to activate a telomere maintenance mechanism (TMM) to allow for indefinite proliferation. Current evidence supports that TMMs, and their associated genetic alterations, are predominantly mutually exclusive, however evidence shows that they can rarely co-occur. Here, we explore the prevalence and functional significance of co-occurring TMM-associated genetic alterations. Methods: Our dataset consisted of 252095 tumor samples across 155 solid tumor types, sequenced as a part of routine clinical care on the FoundationOne®CDx platform. TMM genetic alterations were defined as alterations in ATRX, DAXX, TERTp, TERC, RAD21, and HGF. Somatic mutations were used to calculate tumor mutational burden (TMB) and to determine the dominant trinucleotide mutational signature. A novel tumor heterogeneity (TH) score defined as the ratio of the quartile co-efficient of dispersion to the median cancer cell fraction of evaluable short variants, was calculated. Telomeric content was calculated using TelomereHunter. Results: We first assessed which disease types were enriched in samples with co-occurring TMM alterations (TMM+ samples). These included liver hepatocellular carcinoma (10.1%), skin melanoma (7.3%), bladder urothelial carcinoma (5.2%), and glioblastoma (4.8%). In 92% of all samples with co-occurring TMM alterations, a TERTp mutation was one of the alterations detected. No differences were detected in the median TMB values of TMM+ samples vs samples with either one or no detected TMM alterations (TMM-) within liver hepatocellular carcinomas (3.8 muts/Mb vs 2.5) or within glioblastomas (2.5 muts/Mb vs 2.5). However, in skin melanomas and bladder urothelial carcinomas, median TMB values for TMM+ samples were significantly higher compared to TMM- samples (22.5 muts/Mb vs 11.3 in skin melanomas and 10.0 vs 6.3 in bladder urothelial, p<0.0001 for both diseases). For skin melanomas, a significantly higher proportion of TMM+ samples harbored a UV mutational signature compared to TMM- samples (71.3% vs 52.1%, p<0.0001). Similarly, a significantly higher proportion of TMM+ bladder urothelial carcinoma samples harbored an APOBEC mutational signature compared to TMM- samples (46.0% vs 29.7%, p<0.0001). We also observed that the median TH score was significantly higher in TMM+ vs TMM- samples. In skin melanomas, telomeric content of samples altered in ATRX on top of a TERTp mutation most closely resembled samples altered in TERTp alone and was significantly different from telomeric content of samples altered in ATRX alone. Conclusions: TMM genetic alterations more frequently co-occurred within specific diseases. We focused on four diseases, in two of which no association was observed between TMB and co-occurring TMM alterations. But in the other two, co-occurrences were associated with higher TMB burden and higher TH. Our results suggest that the TERTp pathway prevails in melanoma samples altered in both TERTp and ATRX. Citation Format: Radwa Sharaf, Karthikeyan Murugesan, Garrett M. Frampton, Lee A. Albacker, Meagan Montesion. Co-occurrence of alterations impacting telomere elongation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1434.