1487MO - A pan-sarcoma investigation of genetic alterations associated with high telomeric content

Background

To allow for infinite proliferation, tumor cells need to activate mechanisms for telomere maintenance, such as alternative lengthening of telomeres (ALT). ALT is linked to the loss of ATRX or DAXX. Current evidence supports that sarcomas predominantly use ALT for telomere elongation, at a prevalence rate of 20-60%. However, in our dataset, only 12.3% of sarcomas harbored ATRX/DAXX alterations. Thus, we sought to investigate genomic determinants of high telomeric content beyond the canonical ATRX/DAXX alterations.

Methods

Our sarcoma dataset consisted of 14277 samples across 80 sarcoma types, sequenced as a part of routine clinical care on the FoundationOne® Heme platform. Using TelomereHunter, a tool for the estimation of telomeric content from sequencing data, we determined the telomeric content of sarcoma samples in our cohort and investigated the enrichment of genetic alterations associated with high telomeric content.

Results

Telomeric content varied by sarcoma disease type. We observed a median telomeric content of 622.3 TRPM (telomeric reads per million reads) across all sarcoma types and a range of 787.4. In agreement with previous studies, telomeric content was significantly higher in ATRX-altered sarcomas. We further identified that alterations in 3 genes, RAD51B, GID4, and POT1, were enriched in sarcomas with high telomeric content, specifically within uterus leiomyosarcoma for RAD51B, soft tissue sarcoma for GID4, and soft tissue angiosarcoma samples for POT1. Overall, 84% of RAD51B alterations were deletions, mostly spanning the ATPase domain. In ATRX-mutated uterus leiomyosarcoma, RAD51B alterations exerted an additive effect on telomeric elongation. All detected GID4 alterations were amplifications and we identified the minimal amplified region associated with high telomeric content to be chr17p11.2. All POT1 alterations were short variant mutations. Furthermore, our results demonstrated that RAD51B and POT1 alterations were mutually exclusive with ATRX and DAXX alterations, suggestive of a redundancy between alterations in these genes.

Conclusions

Our results suggest a role played by RAD51B, GID4, and POT1 in telomere elongation in sarcomas and open research opportunities for agents aimed at targeting this pathway.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

R. Sharaf: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. D.X. Jin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. G.M. Frampton: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. L.A. Albacker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. D. Thomas: Financial Interests, Personal, Officer, CEO: Omico; Financial Interests, Personal and Institutional, Other, Commercial and academic partnership: Roche, Pfizer, Eisai, AstraZeneca, Amgen, Foundation Medicine, Inc, Microba, Merck, GMDx, Biotessellate, InterVenn; Financial Interests, Personal and Institutional, Other, Commercial and academic partnership partnership: Abbvie, Eli Lilly, BeiGene, Bayer, Illumina; Financial Interests, Personal, Advisory Role: Health Futures Fund of Australian unity, Maine Cancer Genome Initiative. M. Montesion: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche. All other authors have declared no conflicts of interest.