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Genomic alterations promoting telomere maintenance
Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 30, 2025 · Captured 2026-09-09.
Selected source text with whitespace normalised. This Triangle page is not an NCI PDQ summary. Independent clinical review is pending.
Context: Neuroblastoma / Molecular features of neuroblastoma
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, eventually resulting in the cell’s inability to replicate. Patients whose tumors lack telomere maintenance mechanisms have an excellent prognosis, while patients whose tumors harbored telomere maintenance mechanisms have a substantially worse prognosis.[25] Low-risk neuroblastoma tumors, as defined by clinical/biological features, have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[25-28] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:
MYCN amplification, which is associated with approximately 40% to 50% of high-risk neuroblastoma cases, is sufficient to drive TERT overexpression.[25,26,29]
TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26-28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.
TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26-28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.
Children whose tumors have TERT rearrangements have a poor prognosis, which is comparable to the prognosis of children whose tumors have MYCN amplification.[28]
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TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26-28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.
Chromosome 11q loss and chromosome 1q gain are common in patients with TERT rearrangements.
TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26-28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.
NGS or FISH using break-apart probes may be used to identify TERT rearrangements.[13]
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ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
ALT activation is present in approximately 20% to 25% of newly diagnosed high-risk cases, compared with approximately 5% to 12% of low-risk and intermediate-risk cases.[28,31,32]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
Compared with newly diagnosed cases, the proportion of neuroblastoma cases with ALT-positive tumors was higher in a cohort of patients who relapsed (10% vs. 48%, respectively). This finding may reflect the relatively indolent course of tumors with ALT activation after relapse (see below), compared with the clinical course of other tumors after relapse.[31]
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ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
Like cases with TERT rearrangements, chromosome 11q loss is commonly observed in ALT-positive neuroblastoma. Unique to ALT-positive cases is deletion at chromosome 1q42.2.[12,31]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
Neuroblastoma cases with ALT activation have low TERT expression and can be identified by immunohistochemistry for the ALT-associated promyelocytic nuclear body, by FISH with a telomere probe to visualize telomere ultrabright spots, and by the C-circle assay.[31-33]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
ALT-positive tumors in pediatric populations rarely present before the age of 18 months and occur almost exclusively in older children (median age at diagnosis, approximately 8 years).[28,31] The proportion of neuroblastoma cases with ATRX variants increases with age into the adolescent and young adult populations.[30]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
The prognosis for high-risk patients with ALT activation is as poor as that for patients with MYCN amplification for EFS.[28,31] However, OS is more favorable for patients with ALT activation. The more favorable OS appears to result from a more protracted disease course after relapse, but with long-term survival at 10 to 15 years being as low as that for other patients with high-risk neuroblastoma.[28,31] In one report, EFS and OS for low-risk and intermediate-risk patients with ALT activation were similar to those observed for ALT-positive patients with high-risk disease.[31]
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