<i>NELL2</i>-<i>PAX7</i> Transcriptional Cascade Suggests Activation Mechanism for <i>RAD52</i>-Dependent Alternative Lengthening of Telomeres During Malignant Transformation of Malignant Peripheral Nerve Sheath Tumors: Elongation of Telomeres and Poor Survival

<b>Background</b>: 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. <b>Methods</b>: 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. <b>Results</b>: We identified 22 differentially expressed genes (DEGs) during the malignant transformation of MPNSTs. Among them, <i>NELL2</i> activated <i>PAX7</i>, which sequentially activated <i>RAD52</i>, the recombinase of RAD52-dependent alternative lengthening of telomeres (ALT). <i>RAD52</i> elongated MPNSTs–telomeres (<i>p</i> = 0.017). Otherwise, neither <i>NELL2</i> nor <i>PAX7</i> affected telomere length (<i>p</i> = 0.647 and <i>p</i> = 0.354, respectively). <i>RAD52</i> increased MPNSTs–telomeres length, independently of <i>NELL2</i> and <i>PAX7</i> in multiple analyses (<i>p</i> = 0.021). The group with increased telomere length during the malignant transformation showed inferior overall survival (OS) (HR = 3.809, <i>p</i> = 0.038) to the group without increased telomere length. Accordingly, the group with increased <i>PAX7</i> showed inferior OS (HR = 4.896, <i>p</i> = 0.046) and metastasis-free survival (MFS) (HR = 9.129, <i>p</i> = 0.007) in comparison to the group without increased <i>PAX7</i>; the group with increased <i>RAD52</i> showed inferior MFS (HR = 8.669, <i>p</i> = 0.011) in comparison to the group without increased <i>RAD52</i>. <b>Conclusions</b>: We suggest that the <i>NELL2</i>-<i>PAX7</i> transcriptional cascade activates RAD52-dependent ALT to increase telomere length during the malignant transformation of MPNSTs, resulting in a poor prognosis.