The clinical and functional effects of TERT variants in myelodysplastic syndrome

Abstract

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (p<0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. The majority of variants were missense substitutions and classified as variants of unknown significance (VUS). Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90 percent of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

“…We also identified three lead variants at the TERT locus for which CH risk alleles were associated with longer LTL, a finding corroborated by our MR results linking increased LTL to CH. Interestingly, a recent study found deleterious rare germline TERT variants associated with shorter telomeres in patients with myelodysplastic syndromes 87 . However, compared with conventional myelodysplastic syndromes, these cases displayed a paucity of somatic mutations in DNMT3A (2 of 41) and TET2 (3 of 41 cases), suggesting that evolutionary paths may differ between cases with long versus short telomeres.…”

Telomere-mediated lung disease

“…Thus, the absence of a family history of telomere-mediated disease does not preclude the presence of a germline mutation. TERT mutations may also manifest in children as aplastic anemia and in adults with myelodysplastic syndrome, where they also explain 3–5% of cases ( 54 , 66 , 67 ).…”

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies

“…In telomere biology disorders (TBD), MDS and myeloid leukemia were the most commonly diagnosed cancers, with a median age at diagnosis of 53 years (range of 12–71 years old) ( 11 ). TERT mutations were identified in 2.7% of adult patients with MDS ( 12 ). DDX41 mutations associated with MDS and AML are characterized by presentation in older adulthood, often without any family history ( 13 , 14 ).…”