Telomere maintenance mechanisms are activated in ganglioneuroblastoma and ganglioneuroma

Telomere maintenance mechanisms (TMM) have garnered attention as a mechanism associated with the treatment resistance and poor prognosis of neuroblastoma (NB). Ganglioneuroblastoma (GNB) and ganglioneuroma (GN) are histologically classified as neuroblastic tumors (NTs) along with NB; however, few reports have addressed TMM in GNB and GN. The present study analyzed 321 NTs diagnosed in Japan, including 255 NB cases, 48 GNB cases and 18 GN cases, using a quantitative PCR-based C-circle assay for alternative lengthening of telomeres (ALT) and a telomerase reverse transcriptase (<i>TERT</i>) mRNA expression assay. ALT was identified in 38 NB cases (38/255, 15%) and 6 GNB cases (6/48, 12.5%), but not in GN. High <i>TERT</i> expression was observed in 38% (64/169), 23% (7/31) and 14% (1/7) of NB, GNB and GN cases, respectively. TMM activation, defined as ALT(+) and/or high <i>TERT</i> expression, occurred in 12/48 GNB cases and 1/18 GN cases, particularly in the GNB-nodular type (10/21, 48%), which was similar to 39% (100/255) of NB cases. Furthermore, TMM(+) GNBs exhibited distinct features, including a high frequency of <i>ATRX</i> alterations and a lower frequency of <i>TERT</i> rearrangements. Chromosomal aberration analysis revealed frequent 7q gain, 17q gain and 11q loss in ALT(+) NTs (83%). Overall, TMM serves as a poor prognostic marker for high-risk NB and offers valuable insights for the risk classification of GNBs.