TERT rearrangements in high-risk neuroblastoma induce TERT upregulation and telomerase activity.

  • Major finding:TERT rearrangements in high-risk neuroblastoma induce TERT upregulation and telomerase activity.

  • Concept: Alterations in TERT, MYCN, or ATRX all lead to telomere lengthening in high-risk neuroblastoma.

  • Impact: Telomerase inhibition might be an effective therapy in high-risk neuroblastoma.

Neuroblastomas are malignant pediatric tumors with a low mutation frequency. Recurrent alterations include MYCN amplification and ATRX mutation. Although in about half of cases tumors spontaneously regress or are cured by limited therapy, the remaining cases have poorer outcomes, and the molecular mechanisms that drive high-risk neuroblastoma are not well understood. To characterize structural alterations in high-risk neuroblastoma, Peifer and colleagues performed whole-genome sequencing of 56 neuroblastoma tumors and matched normal controls, which identified four recurrent breakpoint clusters. Three of these clusters were related to known genetic alterations, whereas the fourth was in chromosome 5p15.33 upstream of the telomerase reverse transcriptase (TERT) gene. These latter rearrangements occurred in 21% of tumors and were structurally diverse, including balanced translocations, copy-number gains, high-level amplifications, and chromothripsis; however, these rearrangements did not directly affect the TERT gene or its promoter. TERT rearrangements were exclusively found in high-risk neuroblastomas, mutually exclusive to ATRX and MYCN alterations, and associated with a poor patient outcome and high expression of TERT mRNA. MYCN-amplified tumors also showed high TERT expression, and MYCN knockdown downregulated TERT, suggesting that 5p15.33 rearrangement and MYCN amplification both confer high risk through TERT activation. Chromatin immunoprecipitation sequencing in TERT-rearranged tumors indicated that active enhancer histone modifications were clustered immediately next to the breakpoints, suggesting that rearrangement juxtaposed TERT to strong enhancer elements and induced epigenetic remodeling of the TERT locus. Mechanistically, the high levels of TERT expression were associated with an increase in telomerase activity in TERT-rearranged and MYCN-amplified tumors, which led to telomere lengthening, whereas in ATRX-mutant or other high-risk tumors lacking TERT or MYCN alterations the alternative lengthening of telomeres (ALT) pathway was activated. Altogether, this study identifies recurrent TERT rearrangement and telomere lengthening as an important mechanism characterizing high-risk tumors and supports the development of telomerase inhibitors to treat this aggressive disease.

Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 2015;526:700–4.

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