Researchers conducted a study to characterize the effects of TERT rare variants in patients with myelodysplastic syndrome (MDS) and found them to occur in 2.7% of patients, with possible links to poorer survival. The study results were reported in a recent issue of the journal Blood.

TERT is a gene that encodes telomerase reverse transcriptase. TERT has often been found to be mutated in patients with disorders of involving telomere biology, and MDS is associated with impaired telomere maintenance, according to the researchers, but the genetics involved in telomere length with MDS are not fully known.

The study was based on a cohort of 1514 patients with MDS who were enrolled in The Center for International Blood and Marrow Transplant Research repository and for whom whole peripheral blood DNA samples were available. An additional cohort of 401 patients with non-Hodgkin lymphoma (NHL) with available whole peripheral blood DNA samples was also examined.

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The researchers identified TERT variants in patients with MDS, and they evaluated relationships between TERT variants and telomere length, in addition to survival outcomes following allogeneic transplantation. The researchers also performed functional analyses of TERT variants. To do so, they performed site-directed mutagenesis of human TERT complementary DNA to generate TERT variants for studying human TERT (hTERT) protein expression and homology modeling. Rare variants were those with a maximum allele frequency of <0.001.

From a total of 270 nonsynonymous TERT coding variants found across both patient cohorts, the researchers identified 42 variants they considered rare. Common TERT variants were seen at a similar frequency in both the MDS and NHL cohorts (11.8% versus 11.2%, respectively; P =.79). However, rare variants were seen in 2.7% of patients with MDS, compared with 0.25% of patients with NHL (P <.001). Rare variants of TERT found in patients with MDS were present across sequences related to all structural domains.

Presence of a TERT rare variant was associated with shorter telomere length (P <.001), in addition to a younger age at diagnosis (P =.03), compared with having no TERT variant. Homology modeling suggested that TERT rare variants may be associated with disruptions to domain-specific functions.

Multivariable analysis showed TERT rare variants to be linked to shorter overall survival (hazard ratio [HR] for death, 1.50; 95% CI, 1.04-2.20; P =.03), compared with absence of a TERT rare variant. Patients with TERT rare variants also had an increased risk of NRM (HR, 1.75; 95% CI, 1.13-2.72; P =.01), but their relapse risk was not higher (HR, 0.78; 95% CI, 0.42-1.16; P =.44) than in patients without a TERT rare variant.

“In summary, we show that TERT rare variants impair telomere elongation in cells and are associated with shorter telomeres, younger age at diagnosis, and an increased risk of NRM in MDS patients undergoing allogeneic transplantation,” the researchers concluded in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Reilly CR, Myllymäki M, Redd R, et al. The clinical and functional effects of TERT variants in myelodysplastic syndrome. Blood. 2021;138(10):898-911. doi:10.1182/blood.2021011075