Telomere maintaining germline and somatic variants in thyroid cancer and melanoma

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.

To test the hypothesis that germline LTS-associated PV/LPV are exclusive from functional somatic TERT variants and assess clinical/genetic associations.

Retrospective observational cohort study with/without germline LTS variants, that have somatic sequencing and pathology data.

Participants were enrolled through 18 cancer centers participating in the Oncology Research Information Exchange Network (ORIEN).

995 adults with NMTC and 993 with melanoma between 2013 and 2025. All adult patients at an ORIEN center were offered enrollment.

All patients with NMTC or melanoma are included. There are no required exposures.

The presence/absence of a germline or somatic long-telomere variant; secondary outcomes are associations with tumor stage, telomerase expression, and oncogenes.

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.

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.

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.