The clinical and functional effects of TERT variants in myelodysplastic syndrome

Abstract

Germline pathogenic TERT variants are associated with short telomeres and a heightened risk of developing myelodysplastic syndrome (MDS) among patients with dyskeratosis congenita. The prevalence and clinical significance of TERT variants in MDS patients undergoing allogeneic stem cell transplant is unknown. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) with genetic and clinical characteristics consistent with a germline origin. TERT rare variants occurred in all structural domains and were associated with shorter telomere length (p<0.001) and younger age at MDS diagnosis (p=0.04). No patients with a TERT rare variant had a known telomere biology disorder. In multivariable analyses, 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). Deaths from non-infectious pulmonary causes were more frequent in patients with a TERT rare variant. Across all major structural domains, TERT rare variants demonstrated impaired capacity to elongate telomeres in a cell-based assay. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants likely disrupt domain-specific functions. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Systematic screening for TERT rare variants in MDS patients regardless of age or clinical suspicion could identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches. Cell-based functional characterization of TERT rare variants may facilitate TERT-specific variant classifications guidelines with broad clinical applicability.

A study of Telomerase Reverse Transcriptase rare variants in myeloid neoplasia

“…Despite the lack of known clinical impact or disease association (classified as VUS according to ACMG/Association for Molecular Pathology guidelines 12 and Sherloc criteria 13 ), these alterations led to functional impairment of telomere elongation in vitro and TL in vivo. 11 Our molecular screening conducted on an unselected MN population resulted in a much lower frequency of TERT VUS and very low overlap compared to previous analyses (Figure S2A). 11 We then explored whether the presence of TERT rare variants would lead to the perturbation of the control mechanisms preserving TL, thereby causing telomere shortening.…”

“…11 Our molecular screening conducted on an unselected MN population resulted in a much lower frequency of TERT VUS and very low overlap compared to previous analyses (Figure S2A). 11 We then explored whether the presence of TERT rare variants would lead to the perturbation of the control mechanisms preserving TL, thereby causing telomere shortening. Estimation of TL, possible in 12 patients carrying TERT rare variants, did not reveal differences compared to wild-type cases (n = 1420; Figure 1D) suggesting that cause-effect of these alterations might be undermined by their low prevalence.…”

“…A surprisingly high combined prevalence (41/1514; 2.7%) of rare and non-recurrent germline TERT variants was recently reported in a cohort of patients with MDS undergoing allogeneic HSCT, 11 but none of the carriers exhibited the typical features of classical telomeropathies. Despite the lack of known clinical impact or disease association (classified as VUS according to ACMG/Association for Molecular Pathology guidelines 12 and Sherloc criteria 13 ), these alterations led to functional impairment of telomere elongation in vitro and TL in vivo.…”

The journey of a thousand miles begins with 1 step

“…They cloned all variants, quantified their impact on telomere elongation in cellbased assays, and proved their association with inferior posttransplant outcome. 1 This study has implications for both clinical and translational research. The pathophysiology of MDS has remained largely obscure for a long time.…”

Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders

“…Germline mutations in telomerase and other telomere-related genes are thought to be one of if not the most common known genetic cause of adult-onset myelodysplastic syndromes and possibly acute myeloid leukemia (MDS/AML) (1)(2)(3)(4). In line with this observation, MDS/AML are the most common cancers in patients with inherited mutations in telomerase and other telomere maintenance genes (5,6).…”