TERT – Acute Myeloid Leukemia

Multiple case–control studies have established that common TERT promoter single–nucleotide variants rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03) are associated with increased risk of acute myeloid leukemia in 226 patients versus 806 controls (PMID:26298771). A Romanian cohort of 146 AML patients and 363 healthy individuals failed to detect a risk association for these SNVs but confirmed rs2853669 as an independent predictor of worse overall survival (HR adjusted = 1.54, 95% CI: 1.01–2.35) (PMID:35154531).

Germline hypomorphic TERT coding variants were identified in 11 of 133 consecutive AML patients versus 198 controls (P < 0.0001), with mutation origin confirmed in 5 patients by analysis of nonhematopoietic tissues (PMID:19147845). A larger series of 420 younger AML patients revealed 15 carriers (3.6%) of the recurrent c.3184G>A (p.Ala1062Thr) allele, which correlated with significantly inferior 6-year overall survival (20% vs 41%, p = 0.005) and increased treatment-related mortality (PMID:28331964).

An independent Egyptian cohort of 153 AML cases and 197 controls found c.3184G>A (p.Ala1062Thr) in 18 patients (11.8%) versus 0.5% of controls, associating with lower complete remission (16.7% vs 53.3%), higher relapse (62.5% vs 28.2%) and shorter overall survival (p = 0.001), independent of cytogenetic status and performance score (PMID:25108601).

These data encompass over 700 AML probands of diverse ancestries. Segregation of germline TERT missense alleles in five familial cases supports autosomal dominant inheritance with haploinsufficiency. The TERT variant spectrum in AML is dominated by missense and promoter SNVs, with c.3184G>A (p.Ala1062Thr) recurrent across cohorts.

Functionally, introduction of hypomorphic TERT alleles into telomerase-deficient cells results in reduced enzymatic activity by haploinsufficiency, and promoter SNVs modulate TERT mRNA expression and telomerase activity. Shortened telomeric overhangs and genome instability in AML cells mirror in vitro phenotypes of TERT deficiency.

Integration of robust genetic association with concordant functional data meets ClinGen criteria for a Strong gene–disease association. TERT promoter polymorphisms and hypomorphic variants serve as risk and prognostic biomarkers in AML, and routine genotyping may inform personalized risk stratification and therapeutic guidance.

References

• Oncotarget | 2015 | Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis. PMID:26298771
• | 2022 | Investigating TERT rs2736100 and rs2853669 in Romanian AML patients. PMID:35154531
• Proceedings of the National Academy of Sciences of the United States of America | 2009 | Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. PMID:19147845
• Annals of Hematology | 2017 | The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia. PMID:28331964
• Medical Oncology (Northwood, London, England) | 2014 | Telomerase reverse transcriptase (TERT) A1062T mutation as a prognostic factor in Egyptian patients with acute myeloid leukemia (AML). PMID:25108601

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