Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers

Normal tissue controls are essential for studying disease-specific differential gene expression. However, healthy human controls are typically available only in postmortal/autopsy settings. In cancer research, fragments of pathologically normal tissue adjacent to tumor site are frequently used as the controls. However, it remained largely underexplored how cancers can systematically influence gene expression of the neighboring tissues. Here we performed, to our knowledge, the first pan-cancer high-throughput comparison of molecular profiles for solid tumor-adjacent and autopsy-derived healthy normal tissues. We found a number of systemic molecular differences between autopsy-derived and tumor-adjacent tissues, related to activation of the immune cells, intracellular transport and autophagy, cellular respiration, telomerase activation, p38 signaling, cytoskeleton remodeling, and reorganization of the extracellular matrix. The tumor-adjacent tissues were deficient in apoptotic signaling and negative regulation of cell growth including G2/M cell cycle transition checkpoint. We also detected an extensive rearrangement of the chemical perception network. Molecular targets of 32 and 37 cancer drugs were over- or underexpressed, respectively, in the tumor-adjacent norms. These processes may be driven by molecular events that are correlated between the paired cancers and adjacent normal tissues, that mostly relate to inflammation and regulation of intracellular molecular pathways such as the p38, MAPK, Notch and IGF1 signaling. However, using a model of macaque postmortal tissues we showed that for the 30 minutes - 24-hour time frame at 4C, an RNA degradation pattern in lung biosamples resulted in an artifact differential expression profile for 1140 genes. Thus, such concerns must be addressed in practice.