An abundance of brain-expressed genes show ectopic activation in lung adenocarcinoma

Tumoral transformation processes sometimes include activation of unscheduled gene expression programs in the cancer cells. This is best exemplified by the so-called cancer-testis (CT) genes, a group of genes expressed in testicular germ cells that become activated in tumors of various somatic origins, through a process of DNA demethylation. Here, we explored the possibility that other tissue-specific gene clusters may become ectopically activated in tumors. Lung adenocarcinoma (LUAD) was used as a model, as all necessary transcriptomic datasets were available, including that of AT2 cells, the cell-of- origin of LUAD. We found that besides CT genes, an abundant group of genes expressed in the brain (CB genes, n=63) or in both brain and testis (CBT genes, n=28) become aberrantly activated in LUAD cell lines and tissues. Interestingly, activation of CB and CBT gene clusters was also detected in various other tumor types. Most CB/CBT genes appeared to exert neuronal functions. Moreover, a significant number of them encode antigens involved in neurological paraneoplastic syndromes. Neither neuroendocrine transdifferentiation, which occurs in 10-20% LUAD, nor DNA demethylation appeared to be responsible of the ectopic activation of CB and CBT gene clusters. Instead, prediction tools and depletion experiments identified the REST repressor as a regulator of a number of CB/CBT genes. Conclusion: Together, our data indicate that tumor development is associated with aberrant activation of a brain gene expression program, supporting the assumption that acquisition of neuronal functions might contribute to malignancy.