Alyan Zafar

Background/Objectives: Chondrosarcoma is a clinically heterogeneous malignancy, and the prognostic role of its genetic features remains incompletely defined. While isocitrate dehydrogenase (IDH) mutations are well characterized, the significance of less common alterations—particularly telomerase reverse transcriptase (TERT) promoter mutations—remains unclear. This study aimed to define the genomic profile of chondrosarcoma and evaluate the prognostic relevance of TERT mutations, alone and in combination with IDH mutations. Methods: We retrospectively analyzed 91 patients with chondrosarcoma, including 54 patients with available next-generation sequencing data for genomic analyses. Tumors were assessed for mutations in IDH, TERT, TP53, and groups of genes involved in key cellular functions (e.g., cell cycle control, chromatin regulation). Associations with tumor characteristics were evaluated, recurrence outcomes were assessed using logistic regression, and overall survival was analyzed using Kaplan–Meier and Cox models adjusted for tumor subtype, grade, and size. Results: IDH mutations were present in 52% of tumors; other alterations included TP53 (16%), TERT (7.7%), chromatin-related genes (14%), and cell cycle genes (8.8%). TERT mutations were enriched in dedifferentiated tumors (p = 0.017) and occurred exclusively in grade 3 disease (“p < 0.001”). TERT-mutant tumors were associated with worse overall survival upon unadjusted analysis (HR 7.02, p = 0.024), but not after adjustment (HR 3.81, p = 0.160). All TERT mutations co-occurred with IDH mutations, and this subgroup had particularly poor survival (HR 7.76, p = 0.022), albeit limited by small numbers. Conclusions: These findings suggest that specific mutations, alone or in combination, may influence clinical outcomes by reflecting more aggressive tumor biology. TERT mutations, particularly with concurrent IDH mutations, may identify high-risk patients and complement established prognostic factors. Further validation is needed.

R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary DNA strand in a double-stranded DNA molecule. R-loop formation can occur during natural processes, such as transcription, in which the nascent RNA molecule remains hybridized with the template DNA strand, while the non-template DNA strand is displaced. However, R-loops can also arise due to many non-natural processes, including DNA damage, dysregulation of RNA degradation pathways, and defects in RNA processing. Despite their prevalence throughout the whole genome, R-loops are predominantly found in actively transcribed gene regions, enabling R-loops to serve seemingly controversial roles. On one hand, the pathological accumulation of R-loops contributes to genome instability, a hallmark of cancer development that plays a role in tumorigenesis, cancer progression, and therapeutic resistance. On the other hand, R-loops play critical roles in regulating essential processes, such as gene expression, chromatin organization, class-switch recombination, mitochondrial DNA replication, and DNA repair. In this review, we summarize discoveries related to the formation, suppression, and removal of R-loops and their influence on genome instability, DNA repair, and oncogenic events. We have also discussed therapeutical opportunities by targeting pathological R-loops.