Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype

Emily A. DeBoy, Anna M. Nicosia, Sandya Liyanarachchi, Sheila S. Iyer, Manisha H. Shah, Matthew D. Ringel, Pamela Brock, Mary Armanios

Research output: Contribution to journalArticlepeer-review


Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Original languageEnglish (US)
Pages (from-to)1114-1124
Number of pages11
JournalAmerican journal of human genetics
Issue number6
StatePublished - Jun 6 2024


  • genetic anticipation
  • lymphoid malignancy
  • melanoma
  • papillary thyroid cancer
  • sarcoma
  • shelterin
  • telomerase
  • telomere

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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