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

doi:10.1016/j.ajhg.2024.04.006

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

Am J Hum Genet. 2024 Apr 29:S0002-9297(24)00121-6. doi: 10.1016/j.ajhg.2024.04.006. Online ahead of print.

Authors

Emily A DeBoy¹, Anna M Nicosia², Sandya Liyanarachchi³, Sheila S Iyer², Manisha H Shah⁴, Matthew D Ringel⁵, Pamela Brock⁴, Mary Armanios⁶

Affiliations

¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Molecular Medicine and Therapeutics, Columbus, OH, USA.
⁴ Department of Internal Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁵ Department of Molecular Medicine and Therapeutics, Columbus, OH, USA; Department of Internal Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁶ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: marmani1@jhmi.edu.

PMID: 38688277
DOI: 10.1016/j.ajhg.2024.04.006

Abstract

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.

Keywords: genetic anticipation; lymphoid malignancy; melanoma; papillary thyroid cancer; sarcoma; shelterin; telomerase; telomere.

Grants and funding

T32 GM136577/GM/NIGMS NIH HHS/United States