Telomerase reverse transcriptase (TERT) A1062T mutation as a prognostic factor in Egyptian patients with acute myeloid leukemia (AML)

Abstract

This study aimed to evaluate the incidence and clinical and prognostic impact of TERT A1062T mutation in AML patients treated at Mansoura Oncology Center. Screening for TERT A1062T mutation in exon 15 of the TERT gene was performed on diagnostic DNA samples from 153 AML patients and 197 healthy subjects as a control group by using sequence-specific primers. TERT A1062T mutation was detected in 18 cases out of 153 patients (11.8 %) and in one out of 197 control group subjects (0.51 %). The achievement of complete remission was significantly higher in AML group with wild type as compared to that in the mutant one (53.3 vs 16.7 %, respectively). In addition, the relapse rate was significantly higher in the mutant patients as compared to those with wild type (62.5 vs 28.2 %, respectively). The AML patients with TERT (A1062T) mutation had shorter overall survival than patients with wild type (P = 0.001). In a multivariable analysis, TERT (A1062T) mutational status is independently worse predictor factor (P = 0.007) when controlling for cytogenetic status (P = <0.001), performance status (P = <0.001) and bone marrow blast cells (P = 0.001). In conclusion, TERT A1062T mutation is an independent negative prognostic factor in AML patients. Therefore, molecular testing for TERT A1062T mutation in patients with AML is recommended in order to delineate their prognostic status.

Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis

“…In our cohort of AML patients, the SNV was identified in 10/226 (4.4%) but it was also found in a similar frequency among Swedish population healthy controls 22/806 (2.7%). This mutations did not significantly alter the risk, nor affecting the OS in our AML cohort, contrary to the study by Salah et al where they identified this mutation in 18 of 153 AML patients and only in one in 197 control group subjects [ 38 ]. In the present study we also show that the TERT promoter polymorphism rs2853669 influence OS with a significantly shorter survival in AML patients with the CC genotype.…”

“…None of the other analyzed TERT SNVs in our study showed any association with the risk of having AML. Recently, TERT 1062A> T SNV (rs35719940) was identified as a mutation with prognostic value and shorter overall survival and it was suggested as an independent negative prognostic factor in AML patients [ 38 ]. In our cohort of AML patients, the SNV was identified in 10/226 (4.4%) but it was also found in a similar frequency among Swedish population healthy controls 22/806 (2.7%).…”

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

“…In the past decade, many studies have sought to identify TERT variants in various types of cancer, as these variants could be the driver of carcinogenesis. One of the most commonly found mutation in AML is G>A conversion in codon 1062 situated at exon 15 of the TERT gene, resulting in alanine>threonine substitution (A1062T) [120][121][122][123]. AML patients with A1062T TERT mutation had a relatively poorer prognosis as this mutation is associated with shorter overall survival, higher relapse incidence, and greater rate of treatment-related toxicity [120,121].…”

“…One of the most commonly found mutation in AML is G>A conversion in codon 1062 situated at exon 15 of the TERT gene, resulting in alanine>threonine substitution (A1062T) [120][121][122][123]. AML patients with A1062T TERT mutation had a relatively poorer prognosis as this mutation is associated with shorter overall survival, higher relapse incidence, and greater rate of treatment-related toxicity [120,121]. Epigenetic regulation of TERT has been the focus of many studies as it is believed to aid in the malignant transformation of cells [54].…”

Telomerase exerts physiological and tumor promoting functions by stimulating ribosomal biogenesis

“…Mutations in all three telomerase core components (TERT, TERC and DKC1) have substantial effects on cell proliferation in humans, resulting in stem cell exhaustion, aging phenotypes and cancer [39][40][41][42][43] . Interestingly, mutations that impair telomere function were also found in NHP2 and NOP10, like DKC1, nucleolar factors that are associated with telomerase [44][45][46][47] .…”