Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Importance Non-medullary thyroid cancer (NMTC) and melanoma are associated with inherited long telomeres due to germline pathogenic/likely pathogenic variants (PV/LPV) in POT1 , TINF2 , and ACD resulting in long-telomere syndrome (LTS) and they commonly have somatic TERT promoter mutations. The genetic relationship between these variants and their clinical associations are defined incompletely and may inform clinical practice. Objective To test the hypothesis that germline LTS-associated PV/LPV are exclusive from functional somatic TERT variants and assess clinical/genetic associations. Design Retrospective observational cohort study with/without germline LTS variants, that have somatic sequencing and pathology data. Setting Participants were enrolled through 18 cancer centers participating in the Oncology Research Information Exchange Network (ORIEN). Participants 995 adults with NMTC and 993 with melanoma between 2013 and 2025. All adult patients at an ORIEN center were offered enrollment Exposures All patients with NMTC or melanoma are included. There are no required exposures. Main Outcomes and Measures The presence/absence of a germline or somatic long-telomere variant; secondary outcomes are associations with tumor stage, telomerase expression, and oncogenes. Results Germline and somatic variants in POT1 / TINF2/ACD , somatic TERT promoter variants, TERT fusions, oncogenes, and telomerase mRNA expression were evaluated in 995 NMTC and 993 melanoma patients. In NMTC, 13 (1.5%) had a germline LTS variant while 0/12 with tumor sequencing had somatic TERT promoter variants/fusions. In melanoma, 7 (0.7%) had a LTS variant; 0/2 with tumor sequencing had a TERT promoter variant/ fusion. Meta-analysis including NMTC and melanoma in the current study, a recent thyroid cancer study, and thyroid TCGA, germline LTS-associated PV/LPV and somatic TERT variants/fusions were mutually exclusive (p=0.036). High telomerase mRNA levels were associated with TERT promoter variants/fusions (p<4e-11) and larger NMTC/distant metastases (p=0.016), but not germline LTS variants. NMTCs with somatic TERT promoter variants/fusions had higher tumor mutation burden (p<0.02) versus tumors from patients with a germline LTS variant. TERT promoter mutant variant allele frequency was lower in smaller and non-metastatic vs larger/metastatic NMTC. Conclusion and Relevance Germline LTS-associated variants appear to be exclusive from somatic TERT promoter variants/fusions but are not associated with aggressive NMTC, suggesting common roles in tumorigenesis but different biological impacts. Key points Question Are germline and somatic variants associated with telomere maintenance mutually exclusive and are their biological associations distinct or overlapping? Findings In this cohort study, it was determined that germline variants that cause long telomere syndrome are mutually exclusive from somatic TERT promoter mutations in non-medullary thyroid cancer (NMTC) and melanoma but that the somatic TERT promoter mutations are uniquely associated with more aggressive disease in NMTC. Meaning Despite the mutual exclusivity of germline and somatic telomere maintenance variants in patients with thyroid cancer, the clinical associations are not overlapping, consistent with functional differences supporting the need for individualized clinical counseling.
Source: medRxiv
Institutions: The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, University of Helsinki, University of Colorado Cancer Center, University of Colorado Anschutz, University of Utah, Huntsman Cancer Institute, University of Southern California, USC Norris Comprehensive Cancer Center, Uniformed Services University of the Health Sciences, OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Virginia Medical Center, University of Virginia Cancer Center, University of Virginia, Indiana University School of Medicine
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7162331857