Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk
- 1Stanford University School of Medicine
Abstract
The contribution of telomere length, telomerase activation, and alternative lengthening of telomeres (ALT) to individual sarcoma subtypes remains unclear. We analyzed 11,792 patients with sarcoma sequenced across 19 centers in AACR Project GENIE v20.0, defining telomerase activation as TERT promoter mutation, amplification, or rearrangement and using ATRX/DAXX inactivation as the ALT proxy, with denominators restricted to patients whose assay interrogated the relevant locus. Findings were tested for TERT expression in The Cancer Genome Atlas, for overall survival in MSK-IMPACT 50K, and for replication in an independent Foundation Medicine cohort; Mendelian randomization in FinnGen tested germline telomere length. Telomerase activation (8.8%) and ATRX/DAXX loss (8.0%) segregated by histology and co-occurred less often than expected across subtypes (Mantel-Haenszel odds ratio [OR], 0.52; 95% CI, 0.29 to 0.92). In MDM2-amplified dedifferentiated liposarcoma (DDLPS), telomerase was activated through TERT amplification (17.2%) or rearrangement (2.7%) and never through promoter mutation (0/261), and never co-occurred with ATRX/DAXX loss (0/49; P = .011). TERT-amplified tumors expressed TERT (P = .002), and amplification was largely focal. Telomere maintenance alterations were present in 28.0% of DDLPS versus 8.7% of well-differentiated liposarcoma (P < .001) and predicted shorter overall survival in DDLPS (hazard ratio, 2.04; 95% CI, 1.23 to 3.39; P = .005). ATRX/DAXX loss was more frequent in uterine than extrauterine leiomyosarcoma in GENIE (adjusted OR, 1.96) and in the independent cohort (OR, 1.95; both P < .001). Genetically longer telomeres were associated with liposarcoma (OR per SD, 4.10; 95% CI, 2.15 to 7.81). Telomere maintenance in sarcoma is therefore histology-specific; in liposarcoma it is acquired at dedifferentiation through focal TERT amplification or ALT rather than promoter mutation, and it identifies DDLPS with inferior survival.
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BibTeX
@misc{pan2026somatic,
title = {{Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk}},
author = {M. Pan and J. Chi and M. Y. Zhou and N. Bui and K. Ganjoo},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.26364135},
url = {https://www.medrxiv.org/content/10.64898/2026.09.28.26364135v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk
AU - M. Pan
AU - J. Chi
AU - M. Y. Zhou
AU - N. Bui
AU - K. Ganjoo
PY - 2026
DA - 2026/09/28
PB - medRxiv
DO - 10.64898/2026.09.28.26364135
UR - https://www.medrxiv.org/content/10.64898/2026.09.28.26364135v1
AB - The contribution of telomere length, telomerase activation, and alternative lengthening of telomeres (ALT) to individual sarcoma subtypes remains unclear. We analyzed 11,792 patients with sarcoma sequenced across 19 centers in AACR Project GENIE v20.0, defining telomerase activation as TERT promoter mutation, amplification, or rearrangement and using ATRX/DAXX inactivation as the ALT proxy, with denominators restricted to patients whose assay interrogated the relevant locus. Findings were tested for TERT expression in The Cancer Genome Atlas, for overall survival in MSK-IMPACT 50K, and for replication in an independent Foundation Medicine cohort; Mendelian randomization in FinnGen tested germline telomere length. Telomerase activation (8.8%) and ATRX/DAXX loss (8.0%) segregated by histology and co-occurred less often than expected across subtypes (Mantel-Haenszel odds ratio [OR], 0.52; 95% CI, 0.29 to 0.92). In MDM2-amplified dedifferentiated liposarcoma (DDLPS), telomerase was activated through TERT amplification (17.2%) or rearrangement (2.7%) and never through promoter mutation (0/261), and never co-occurred with ATRX/DAXX loss (0/49; P = .011). TERT-amplified tumors expressed TERT (P = .002), and amplification was largely focal. Telomere maintenance alterations were present in 28.0% of DDLPS versus 8.7% of well-differentiated liposarcoma (P < .001) and predicted shorter overall survival in DDLPS (hazard ratio, 2.04; 95% CI, 1.23 to 3.39; P = .005). ATRX/DAXX loss was more frequent in uterine than extrauterine leiomyosarcoma in GENIE (adjusted OR, 1.96) and in the independent cohort (OR, 1.95; both P < .001). Genetically longer telomeres were associated with liposarcoma (OR per SD, 4.10; 95% CI, 2.15 to 7.81). Telomere maintenance in sarcoma is therefore histology-specific; in liposarcoma it is acquired at dedifferentiation through focal TERT amplification or ALT rather than promoter mutation, and it identifies DDLPS with inferior survival.
ER -