Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk

TERT

Telomerase activation through TERT amplification or rearrangement (never promoter mutation in dedifferentiated liposarcoma) or the ALT pathway with ATRX/DAXX loss, mutually exclusive

This preprint analysed 11,792 patients with sarcoma sequenced across 19 centers (AACR Project GENIE v20.0), with validations in TCGA (TERT expression), MSK-IMPACT 50K (overall survival) and an independent Foundation Medicine cohort, and Mendelian randomization in FinnGen for germline telomere length. Telomerase activation (8.8%) and ATRX/DAXX loss (8.0%) were mutually exclusive (OR 0.52; 95% CI 0.29-0.92) and segregated by histology. In MDM2-amplified dedifferentiated liposarcoma (DDLPS), telomerase was activated through TERT amplification (17.2%) or rearrangement (2.7%), never promoter mutation (0/261). Telomere maintenance alterations were present in 28.0% of DDLPS versus 8.7% of well-differentiated liposarcoma and predicted shorter overall survival in DDLPS (HR 2.04; 95% CI 1.23-3.39). Genetically longer telomeres were associated with liposarcoma (OR per SD 4.10; 95% CI 2.15-7.81).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Most of the work is somatic (GENIE tumor panels): the germline component is limited to a Mendelian randomization whose OR confidence interval (2.15-7.81) is wide, and it does not concern carriers of pathogenic variants. The prognostic marker in DDLPS (HR 2.04) is consistent across cohorts, but this is a preprint not yet peer-reviewed and with no demonstrated management consequence. Its relevance for constitutional oncogenetics therefore remains indirect: to be re-read on publication.

Analysis by Dr Thibaut Benquey