Neuroblastoma is a malignant pediatric tumor of the sympathetic nervous system. While roughly half of these tumors regress spontaneously or are cured by limited therapy, high-risk neuroblastomas have an unfavorable clinical course, despite intensive multimodal treatment. The genetic basis of the various clinical subtypes of the disease has remained largely elusive. To gain a better understanding of the genetic events that may drive neuroblastoma tumorigenesis, we here performed whole-genome sequencing of 42 primary neuroblastomas (high-risk, n = 25; low-risk, n = 17). We identified genomic rearrangements affecting chromosome 5p15.22 in a 50 kb region centromeric of the human telomerase reverse transcriptase gene (TERT) in 8 tumors. The rearrangements occurred only in high-risk neuroblastomas (8/25, 32%) in mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumor type. In an Independent validation cohort of 14 high-risk neuroblastomas, we detected rearrangements of the TERT locus in 4 additional samples. The structure of the rearrangements varied greatly, including balanced translocations, low-level copy number gains, focal amplifications and chromothripsis. Independent of the copy number at this region, all alterations consistently induced massive transcriptional up-regulation of TERT and of three additional genes located in close proximity to the chromosomal breakpoint. By contrast, MYCN-amplified tumors showed only up-regulation of TERT itself, suggesting that both MYCN amplification and TERT rearrangements converge on TERT activation. Supporting a functional role of TERT, both MYCN-amplified neuroblastoma cell lines and cell lines bearing TERT rearrangements exhibited elevated TERT expression and enzymatic telomerase activity in comparison to cell lines without these aberrations. Our findings show that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma, and places telomerase activation in the center of transformation in a large fraction of these tumors. More broadly, our findings provide a mechanistic basis for molecular diagnosis and therapy of this deadly pediatric tumor entity.

Citation Format: Martin Peifer, Frederik Roels, Falk Hertwig, Roopika Menon, Andrea Kraemer, Reinhard Buettner, Sven Perner, Alexander Schramm, Johannes H. Schulte, Frank Westermann, Roman K. Thomas, Matthias Fischer. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-210. doi:10.1158/1538-7445.AM2015-LB-210