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

Abstract

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 CBTgene 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 CBTgene 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.