Backgroud: We have reported telomere biology in NBL: telomerase activation and alternative lengthening of telomere (ALT) due to ATRX/DTXX mutations. Recently, genomic rearrangements at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT) were found in some group of unfavorable NBLs. Therefore, we analyzed alteration of TERT promoter lesion (PL) in our NBL series.
Methods: We analyzed the alterations of TERT-PL using SNP array or next generation sequencing in 146 NBL samples whose telomere length, telomerase activity, TERT expression, ATRX/DTXX mutations as well as other biological factors (MYCN, ALK, etc.) were already analyzed. Among them, 80 were diagnosed under 18 months and 34 were detected by mass-screening. INRGSS classification showed 60 L1, 30 L2, 47 M and 9 MS.
Results: In 11 ALT-activated tumors with elongated telomere (15 - 40 kb) and ATRX/DAXX alterations showed no alteration of TERT-PL. In the 135 remaining cases, telomere length were under 15 kb and high expression of telomerase/TERT was detected in 63 tumors consisting of 5 L1, 10 L2, 46 M and 2 MS tumors. All 28 MYCN amplified tumors showed high telomerase/TERT expression but alteration of TERT-PL were detected in only 4 of them. In MYCN non-amplified tumors, 29 of 35 cases with high telomerase/TERT expression and 9 of 72 cases without high telomerase/ TERT expression had alteration of TERT-PL (P <0.01). The outcome of the cases with high telomerase telomerase/ TERT expression showed significantly worse than others (P <0.01). Interestingly, 7 of 34 screening-detected tumors and 13 of 80 tumors diagnosed under 18 months had alteration of TERT-PL.
Conclusion: In NBLs, alteration of TERT-PL might activate TERT expression in unfavorable cases without MYCN amplification. As MYCN activates TERT expression, the stabilization of telomere by ALT or high telomerase activity might be directly correlated with unfavorable tumors. Thus, a better understanding of telomere biology and developing of therapeutic strategies for telomere-stable NBLs may help to improve the outcome of NBL patients.