Exploring the involvement of the neurodegenerative disease-related protein TDP-43 in CNS vs other cancers

TDP-43 is an RNA-binding protein (RBP) that, amongst other functions, participates in mRNA metabolism. It is a key player in neurodegenerative diseases like frontotemporal dementia and amyotrophic lateral sclerosis. Although recent evidence suggests a potential role in other pathogenic processes, the involvement of this protein in cancer is still unclear. In this work, we aimed to 1) investigate the genes/proteins and pathways associated with differential expression of TDP-43 in the CNS cancers and whether they are conserved in other non-CNS cancers, 2) explore correlations with clinicopathological factors, and 3) analyze mutations in the TARDBP gene. For this purpose, we interrogated the CPTAC datasets using cBioportal to stratify samples according to the 25% and 75% quartiles or median TDP-43 expression. RNA splicing and DNA repair were the top pathways present in groups with high TDP-43 expression, consistent with the role of TDP-43 in these processes. Moreover, high TDP-43 expression positively associated with aggressive breast and pediatric cancer types. Lastly, we found low mutational frequency in TARDBP across all studied cancers (generally <1%). Our data is in line with the notion that abnormal RBP expression or function amplify the effects of cancer driver genes, accelerate tumor progression, and promote aggressiveness. Here, we provide evidence for a potential role of TDP-43 in cancer that deserves further investigation.