DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

Removal of the proliferation component of gene expression by proliferating cell nuclear antigen (PCNA) adjustment via statistical methods has been addressed in numerous survival prediction studies for breast cancer and all cancers in the Cancer Genome Atlas (TCGA). These studies indicate that the removal of proliferation in gene expression by PCNA adjustment removes the statistical significance for predicting overall survival (OS) when gene selection is performed on a genome-wide basis. Since cancers become addicted to DNA repair as a result of forced cellular replication, increased oxidation, and repair deficiencies from oncogenic loss or genetic polymorphisms, we hypothesized that PCNA adjustment of DNA repair gene expression does not remove statistical significance for OS prediction. The rationale and importance of this translational hypothesis is that new lists of repair genes which are predictive of OS can be identified to establish new targets for inhibition therapy. A candidate gene approach was employed using TCGA RNA-Seq data for 121 DNA repair genes in 8 molecular pathways to predict OS for 18 cancers. Statistical randomization test results indicate that after PCNA adjustment, OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. These findings suggest that removal of the proliferation signal in expression by PCNA adjustment does not remove statistical significance for predicting OS. In conclusion, it is likely that previous studies on PCNA adjustment and survival were biased because genes identified through a genome-wide approach are strongly co-regulated by proliferation.