- Transcriptional Cascade Suggests Activation Mechanism for -Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival.

: In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem; here, telomeres serve as a buffer against DNA loss. Thus, the activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. : We compared neurofibroma (NF, benign) and malignant peripheral nerve sheath tumors (MPNSTs) occurring in the same patient with type 1 neurofibromatosis, where each NF-MPNST pair shared the same genetic background and differentiation lineage; this minimizes the genetic bias and contrasts only those changes that are related to malignant transformation. A total of 20 NF-MPNST pairs from 20 NF1 patients were analyzed. Whole-transcriptome sequencing (WTS) was conducted to profile the transcriptional relationship, and whole-genome sequencing (WGS) was performed to measure the telomere length. : We identified 22 differentially expressed genes (DEGs) during the malignant transformation of MPNSTs. Among them, activated , which sequentially activated , the recombinase of RAD52-dependent alternative lengthening of telomeres (ALT). elongated MPNSTs-telomeres ( = 0.017). Otherwise, neither nor affected telomere length ( = 0.647 and = 0.354, respectively). increased MPNSTs-telomeres length, independently of and in multiple analyses ( = 0.021). The group with increased telomere length during the malignant transformation showed inferior overall survival (OS) (HR = 3.809, = 0.038) to the group without increased telomere length. Accordingly, the group with increased showed inferior OS (HR = 4.896, = 0.046) and metastasis-free survival (MFS) (HR = 9.129, = 0.007) in comparison to the group without increased ; the group with increased showed inferior MFS (HR = 8.669, = 0.011) in comparison to the group without increased . : We suggest that the - transcriptional cascade activates RAD52-dependent ALT to increase telomere length during the malignant transformation of MPNSTs, resulting in a poor prognosis.