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

Abstract

Removal of the proliferation component of gene expression by proliferating cell nuclearantigen (PCNA) adjustment via statistical methods has been addressed in numerous survivalprediction studies for breast cancer and all cancers in the Cancer Genome Atlas (TCGA). Thesestudies indicate that the removal of proliferation in gene expression by PCNA adjustment removesthe statistical significance for predicting overall survival (OS) when gene selection is performed ona genome-wide basis. Since cancers become addicted to DNA repair as a result of forced cellularreplication, increased oxidation, and repair deficiencies from oncogenic loss or geneticpolymorphisms, we hypothesized that PCNA adjustment of DNA repair gene expression does notremove statistical significance for OS prediction. The rationale and importance of this translationalhypothesis is that new lists of repair genes which are predictive of OS can be identified to establishnew targets for inhibition therapy. A candidate gene approach was employed using TCGARNA-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 predictedsignificantly by sets of DNA repair genes for 61% (11/18) of the cancers. These findings suggest thatremoval of the proliferation signal in expression by PCNA adjustment does not remove statisticalsignificance for predicting OS. In conclusion, it is likely that previous studies on PCNA adjustmentand survival were biased because genes identified through a genome-wide approach are stronglyco-regulated by proliferation.

Analysis of translesion polymerases in colorectal cancer cells following cetuximab treatment: A network perspective

“…had shown how cetuximab‐treated CRC cell lines have transiently higher levels of mutagenic polymerases and lower levels of MMR proteins 14 while another study on COSMIC signatures associated with cetuximab‐treated CRC showed no significant increase in SBS3 or SBS6 or SBS15 signatures, which are associated with loss of MMR activity 42 . Moreover, an earlier transcriptome study on PCNA and TLS polymerases 43 also identified a co‐regulation of DNA repair genes and TLS polymerases. These findings drove our exploration of whether a cetuximab‐specific transcriptional response exists as well as whether mutagenic polymerases and MMR proteins are indeed co‐regulated.…”

The Proliferating Cell Nuclear Antigen (PCNA) Transcript Variants as Potential Relapse Markers in B-Cell Acute Lymphoblastic Leukemia

“…Finally, Leif E. Peterson and Tatiana Kovyrshina performed metagene analysis and observed that PCNA predicted that overall survival mediates DNA repair adjustment in diverse cancer types, including breast, cervical, colorectal, liver, lung, small cell lung, ovarian, melanoma, renal, stomach, and uterine cancer [ 64 ]. In addition, Guo, J. L et al observed the overexpression of PCNA in a series of cases of breast cancer [ 65 ] and Dan-Dan, Li et al observed it in hepatocellular carcinoma [ 46 ].…”