Recurrent COQ8B-NUMBL Fusions are the Result of Transcriptional Readthrough Events Frequently Found in Solid Tumors

Gene fusions are vital in oncogenesis, although they are rare and represent the sole drivers in a minor fraction of cancers. These fusions often stem from genomic rearrangements, notably translocations, which either enhance oncogenic functions or diminish tumor suppressor gene expression. Their detection and interpretation is important for diagnostic and therapeutic stratification efforts. In this context, the proposed ADCK4(COQ8B)- NUMBL gene fusion has been suggested as a frequent event driving cutaneous squamous cell carcinoma (cSCC) development. However, our analysis contests this assertion, demonstrating that COQ8B-NUMBL fusions observed in cSCC are not the result of genomic rearrangements but rather arise from transcriptional readthrough events between adjacent genes on chromosome 19. Our study, consisting of RNA sequencing data from a diverse range of solid tumors, challenges the (clinical) relevance of COQ8B-NUMBL fusions. Notably, we observe a substantial prevalence (40.8%) of these fusion transcripts across all tested tumor types. Furthermore, our findings reveal a significant co-occurrence (36.8%) between established oncogenic drivers and the COQ8B-NUMBL transcriptional readthrough event, suggesting this is not a driver in carcinogenesis. These insights highlight the importance of discerning between genuine genomic rearrangements and transcriptional artifacts to refine our understanding of oncogenic mechanisms. Overall, our study underscores the need for cautious interpretation of fusion events and advocates for comprehensive fusion analyses to elucidate their true biological significance in cancer pathogenesis.

Keywords: COQ8B-NUMBL; ADCK4; Gene Fusion; Transcriptional Readthrough; Oncogenesis; Solid Tumor

Abbreviations: cSCC: cutaneous squamous cell carcinoma