Telomere maintaining germline and somatic variants in thyroid cancer and melanoma

Germline POT1/TINF2/ACD variants (long-telomere syndrome) and somatic TERT promoter variants/fusions are mutually exclusive in non-medullary thyroid cancer and melanoma — distinct oncogenic mechanisms converging on telomere lengthening

In a retrospective study of 995 non-medullary thyroid cancers (NMTC) and 993 melanomas from 18 ORIEN centers, germline pathogenic variants in POT1, TINF2, and ACD (long-telomere syndrome) were found in 1.5% of NMTCs and 0.7% of melanomas. These germline LTS variants and somatic TERT promoter variants/fusions were mutually exclusive (p=0.036 in meta-analysis). Germline LTS variants are not associated with aggressive NMTC, in contrast to somatic TERT variants correlating with high TMB and advanced stage.

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

The demonstration of mutual exclusivity between germline LTS and somatic TERT is biologically important: it suggests both mechanisms activate the same oncogenic pathway but do not accumulate. For clinicians, young NMTC or melanoma patients should have germline workup including POT1/TINF2/ACD. The absence of germline LTS association with aggressive prognosis is reassuring. Preprint to follow for confirmation.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Journal quality: 0/1 · Preprint: -1 → Total: 6/10