Constitutional Telomerase-Associated Gene Variants in Pediatric Acute Myeloid Leukemia (AML)

Telomerase is an enzyme complex that maintains telomeric DNA, the TTAGGG repeats localized to chromosome ends. Defects in telomerase result in abnormally short telomeres in somatic cells, leading to early cell senescence, chemosensitivity, and susceptibility to genomic instability. Germline telomerase mutations are associated with a spectrum of disorders including idiopathic pulmonary fibrosis, familial liver disease, aplastic anemia, myelodysplastic syndrome (MDS), and dyskeratosis congenita, which confers a 90% lifetime risk for bone marrow failure, a 200-fold risk for AML, and a 2500-fold risk for MDS. These disorders have a variable clinical phenotype, but pronounced telomere shortening is a universal finding. Of note, enrichment of specific telomerase variants is observed in adults with hematologic malignancies. Our goal is to investigate the role of germline telomerase variants in pediatric AML development and treatment-related toxicities. We hypothesize that deleterious germline telomerase variants occur in children with AML and are associated with a telomere biology disorder phenotype. Exposure to chemotherapy and/or transplant may accelerate telomere shortening and manifestation of disease phenotype in affected individuals.

This exploratory analysis will determine (1) the frequency of germline telomerase variants in our local pediatric AML population (2) the implication of these variants on telomerase function, and (3) whether variants are associated with a telomere biology disorder phenotype. We are sequencing the exons and flanking intronic regions of four telomerase-related genes, TERT, DKC1, TERC, and TINF2, in germline pediatric AML samples (n=100), and functionally characterizing all novel variants. We are reviewing all cases blinded to telomerase variant status for clinical evidence characteristic of a telomere biology disorder.

To date, out of the first 88 subjects sequenced, 12 constitutional heterozygous variants resulting in missense changes or deletions were found in 19 subjects (21.6%). Of the variants found, 7 are novel, and several represent rare variants observed in adult populations with hematologic malignancies. Among the 62 subjects that have undergone blinded chart review, clinical characteristics of telomere biology disorders were noted in subjects both with and without variants. In subjects with variants, the most predictive characteristics were (1) nail dysplasia, skin hyperpigmentation, and oral leukoplakia, (2) persistent liver or pulmonary disease of unknown etiology, and (3) delays in chemotherapy of more than 2 months due to cytopenias.

Presence of deleterious telomerase variants may be susceptibility loci in pediatric AML. Our results suggest that further investigation of the disease phenotypes associated with these variants is warranted.

No relevant conflicts of interest to declare.