A Combined Epithelial Mesenchymal Transformation and DNA Repair Gene Panel in Colorectal Cancer With Prognostic and Therapeutic Implication

BackgroundEpithelial mesenchymal transformation (EMT) and DNA repair status represent intrinsic features of colorectal cancer (CRC) and are associated with patient prognosis and treatment responsiveness. We sought to develop a combined EMT and DNA repair gene panel with potential application in patient classification and precise treatment.MethodsWe comprehensively evaluated the EMT and DNA repair patterns of 1,652 CRC patients from four datasets. Unsupervised clustering was used for classification. The clinical features, genetic mutation, tumor mutation load, and chemotherapy as well as immunotherapy sensitivity among different clusters were systematically compared. The least absolute shrinkage and selection operator regression method was used to develop the risk model.ResultsThree distinct CRC clusters were determined. Clustet1 was characterized by down-regulated DNA repair pathways but active epithelial markers and metabolism pathway and had intermediate prognosis. Clustet2 was characterized by down-regulated both epithelial markers and DNA repair pathways and had poor outcome. Clustet3 presented with activation of DNA repair pathway and epithelial markers had favorable prognosis. Clustet1 might benefit form chemotherapy and Clustet3 had a higher response rate to immunotherapy. An EMT and DNA repair risk model related to prognosis and treatment response was developed.ConclusionsThis work developed and validated a combined EMT and DNA repair gene panel for CRC classification, which may be an effective tool for survival prediction and treatment guidance in CRC patients.

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Relationship between DNA repair gene XPD751 single-nucleotide polymorphisms and prognosis of colorectal cancer

Genetics and Molecular Research ◽

10.4238/2015.may.22.8 ◽

2015 ◽

Vol 14 (2) ◽

pp. 5390-5398 ◽

Cited By ~ 6

Author(s):

Y. Dong ◽

J.W. Liu ◽

Y.J. Gao ◽

T. Zhou ◽

Y.M. Chen

Keyword(s):

Colorectal Cancer ◽

Dna Repair ◽

Single Nucleotide Polymorphisms ◽

Nucleotide Polymorphisms ◽

Repair Gene ◽

Single Nucleotide ◽

Dna Repair Gene

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

10.20944/preprints201902.0042.v1 ◽

2019 ◽

Author(s):

Leif Peterson ◽

Tatiana Kovyrshina

Keyword(s):

Gene Expression ◽

Dna Repair ◽

Gene Selection ◽

P Value ◽

Survival Prediction ◽

Dna Repair Genes ◽

Repair Gene ◽

A Genome ◽

Dna Repair Gene ◽

Repair Genes

Removal of the proliferation component of gene expression by PCNA adjustment has been addressed in numerous survival prediction studies for breast cancer and all cancers in the TCGA. These studies indicate that widespread co-regulation of proliferation upwardly biases survival prediction when gene selection is performed on a genome-wide basis. In addition, removal of the correlative effects of proliferation does not reduce the random bias associated with survival prediction using random gene selection. Since most 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 pursued an investigation to remove the proliferation component of expression in DNA repair genes to determine survival prediction. This translational hypothesis-driven focus on DNA repair genes is directly amenable to finding new sets of DNA repair genes that could potentially be studied for inhibition therapy. Overall survival (OS) prediction was evaluated in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene expression were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Interestingly, PARP1 was not a significant predictor of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic cancers for inhibition therapy may be AML, colorectal, and renal papillary, because of potentially less confounding due to lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer for inhibition therapy is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications in DNA repair genes. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.

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