Molecular Evidence for the Inverse Comorbidity between Central Nervous System Disorders and Cancers Detected by Transcriptomic Meta-analyses

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions. We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways. Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.Author Summary: A lower-than-expected probability of developing certain types of Cancer has been observed in patients with CNS disorders, including Alzheimer's disease, Parkinson's disease or Schizophrenia. Understanding such a protective effect could be the key to finding novel treatments for both types of conditions, for instance thanks to drug repurposing. However, little is known about the underlying mechanisms for these intriguing inverse comorbidities. Although environmental causes, drug treatments or lower screening surveys might contribute to the inverse comorbidity between complex disorders, we propose that inverse comorbidity is, at least in part, due to genetic factors.