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Volume 26
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10.3390/ijms26157208
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations

by
Louis M. Gibson
1,2,†,
Phanithan Konda
3,†,
Hunter J. Bliss
4,
Devi D. Nelakurti
2,5,
Golrokh C. Mirzaei
6,
Renee A. Bouley
7,
Jing J. C. Wang
8,* and
Ruben C. Petreaca
2,9,*
1
Neuroscience Undergraduate Program, The Ohio State University, Columbus, OH 43210, USA
2
The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
3
College Credit Plus Program, The Ohio State University, Columbus, OH 43210, USA
4
Biology Undergraduate Program, The Ohio State University, Marion, OH 43302, USA
5
Biomedical Science Undergraduate Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA
6
Department of Computer Science and Engineering, The Ohio State University, Marion, OH 43302, USA
7
Department of Chemistry and Biochemistry, The Ohio State University, Marion, OH 43302, USA
8
Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
9
Department of Molecular Genetics, The Ohio State University, Marion, OH 43302, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work
Int. J. Mol. Sci. 2025, 26(15), 7208; https://doi.org/10.3390/ijms26157208
Submission received: 27 June 2025 / Revised: 17 July 2025 / Accepted: 22 July 2025 / Published: 25 July 2025
(This article belongs to the Special Issue Exploring the Genetics and Genomics of Complex Diseases)
Versions Notes

Abstract

DNA polymerase epsilon (POLe) is the leading strand replicative polymerase. POLe mutations located primarily in the proofreading domain cause replication errors and increase mutation burden in cancer cells. Consequently, POLe has been classified as a cancer driver gene. Certain POLe frameshift mutations that affect the proofreading domain are purified in cancer cells, but point mutations in other domains have also been reported. Here we use an artificial intelligence algorithm to determine what other mutations co-occur with POLe mutations in colorectal cancers. We partitioned POLe mutations into driver, passenger, and WT (no mutation), then assessed mutations in other genes in these three groups. We found that a driver POLe mutation is not likely to associate with driver mutations in other genes. Thus, driver mutations in colorectal cancers appear to purify in a manner that is independent of POLe. Mutations that affect POLe function do not necessarily increase the frequency of driver mutations in other genes. Structural analysis shows that many POLe driver mutations affect coordination of the Mg2+ ion in the active site. Our data show that the accumulation of colorectal cancer mutations is driven by complex factors.
Keywords: colorectal cancer; polymerase epsilon; driver mutation colorectal cancer; polymerase epsilon; driver mutation

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MDPI and ACS Style

Gibson, L.M.; Konda, P.; Bliss, H.J.; Nelakurti, D.D.; Mirzaei, G.C.; Bouley, R.A.; Wang, J.J.C.; Petreaca, R.C. Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations. Int. J. Mol. Sci. 2025, 26, 7208. https://doi.org/10.3390/ijms26157208

AMA Style

Gibson LM, Konda P, Bliss HJ, Nelakurti DD, Mirzaei GC, Bouley RA, Wang JJC, Petreaca RC. Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations. International Journal of Molecular Sciences. 2025; 26(15):7208. https://doi.org/10.3390/ijms26157208

Chicago/Turabian Style

Gibson, Louis M., Phanithan Konda, Hunter J. Bliss, Devi D. Nelakurti, Golrokh C. Mirzaei, Renee A. Bouley, Jing J. C. Wang, and Ruben C. Petreaca. 2025. "Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations" International Journal of Molecular Sciences 26, no. 15: 7208. https://doi.org/10.3390/ijms26157208

APA Style

Gibson, L. M., Konda, P., Bliss, H. J., Nelakurti, D. D., Mirzaei, G. C., Bouley, R. A., Wang, J. J. C., & Petreaca, R. C. (2025). Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations. International Journal of Molecular Sciences, 26(15), 7208. https://doi.org/10.3390/ijms26157208

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