DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity
Open accessAbstract
Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase ε have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in POLE lead to impaired proofreading intrinsic to Pol ε during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol ε have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these POLE mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a POLE mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in POLE deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here.
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The abundance of mutation-associated neoantigens identified in tumors with mutations in POLE or POLD1 makes them heavily immunogenic, allowing them to be potentially sensitive to immune checkpoint inhibition.
“For this reason, the abundance of mutation-associated neoantigens identified in tumors with mutations in POLE or POLD1 makes them heavily immunogenic. This, in turn, allows them to be potentially sensitive to immune checkpoint inhibition [166].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [166]
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Cites
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
Integrated genomic characterization of endometrial carcinoma
The Cancer Genome Atlas Research Network, & Levine, D. A. (2013) · Nature · doi:10.1038/nature12113 · Cited by 5,784 · see citing works
Palles, C., Cazier, J., Howarth, K. M., Domingo, E., Jones, A. M., Broderick, P., Kemp, Z., Spain, S. L., Guarino, E., Salguero, I., et al. (2012) · Nature Genetics · doi:10.1038/ng.2503 · Cited by 995 · see citing works
Howitt, B. E., Shukla, S. A., Sholl, L. M., Ritterhouse, L. L., Watkins, J. C., Rodig, S. J., Stover, E. H., Strickland, K. C., D’Andrea, A. D., Wu, C. J., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2015.2151 · Cited by 687 · see citing works
Domingo, E., Freeman-Mills, L., Rayner, E., Glaire, M., Briggs, S., Vermeulen, L., Fessler, E., Medema, J. P., Boot, A., Morreau, H., et al. (2016) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(16)30014-0 · Cited by 308 · see citing works
Briggs, S., & Tomlinson, I. P. M. (2013) · The Journal of Pathology · doi:10.1002/path.4185 · Cited by 278 · see citing works
Shinbrot, E., Henninger, E. E., Weinhold, N., Covington, K. R., Goksenin, A. Y., Schultz, N. D., Chao, H., Doddapaneni, H., Muzny, D. M., Gibbs, R. A., et al. (2014) · Genome Research · doi:10.1101/gr.174789.114 · Cited by 272 · see citing works
Bellido, F., Pineda, M., Aiza, G., Valdés‐Mas, R., Navarro, M., Puente, D. A., Pons, T., González, S., Iglesias, S. L., Darder, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.75 · Cited by 264 · see citing works
Stadler, Z. K., Battaglin, F., Middha, S., Hechtman, J. F., Tran, C., Cercek, A., Yaeger, R. D., Segal, N. H., Varghese, A. M., Reidy‐Lagunes, D. L., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.1067 · Cited by 236 · see citing works
DNA damage tolerance: a double-edged sword guarding the genome.
Ghosal, G., & Chen, J. (2013) · PubMed · doi:10.3978/j.issn.2218-676x.2013.04.01 · Cited by 204 · see citing works
Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored
Li, S. K. H., & Martín, A. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.02.003 · Cited by 189 · see citing works
Meng, B., Hoang, L. N., McIntyre, J. B., Duggan, M. A., Nelson, G. S., Lee, C., & Köbel, M. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.05.006 · Cited by 182 · see citing works
Therapeutic Targeting of the DNA Mismatch Repair Pathway
Martin, S. A., Lord, C. J., & Ashworth, A. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0821 · Cited by 160 · see citing works
Edwards, S., Li, C. M., Levy, D. L., Brown, J. A., Snow, P. M., & Campbell, J. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.8.2733-2748.2003 · Cited by 88 · see citing works
Leichman, L., Groshen, S. G., O’Neil, B. H., Messersmith, W. A., Berlin, J. D., Chan, E. W., Leichman, C. G., Cohen, S. J., Cohen, D. J., Lenz, H., et al. (2016) · The Oncologist · doi:10.1634/theoncologist.2015-0319 · Cited by 80 · see citing works
Wimmer, K., Beilken, A., Nustede, R., Ripperger, T., Lamottke, B., Ure, B., Steinmann, D., Reineke‐Plaaß, T., Lehmann, U., Zschocke, J., et al. (2016) · Familial Cancer · doi:10.1007/s10689-016-9925-1 · Cited by 74 · see citing works
Ahn, S., Ansari, A. A., Kim, J., Kim, D., Chun, S., Kim, J., Kim, T. W., Park, I. J., Yu, C. S., & Jang, S. J. (2016) · Oncotarget · doi:10.18632/oncotarget.11862 · Cited by 71 · see citing works
Mutations in POLE and survival of colorectal cancer patients – link to disease stage and treatment
Stenzinger, A., Pfarr, N., Endris, V., Penzel, R., Jansen, L., Wolf, T. A., Herpel, E., Warth, A., Klauschen, F., Kloor, M., et al. (2014) · Cancer Medicine · doi:10.1002/cam4.305 · Cited by 68 · see citing works
Yoshida, R., Miyashita, K., Inoue, M., Shimamoto, A., Yan, Z., Egashira, A., Oki, E., Kakeji, Y., Oda, S., & Maehara, Y. (2010) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.216 · Cited by 65 · see citing works
PARP inhibitors in breast cancer: BRCA and beyond.
Rios, J. A., & Puhalla, S. (2011) · PubMed · Cited by 50 · see citing works
PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond
Banerjee, S. N., & Kaye, S. B. (2011) · Current Oncology Reports · doi:10.1007/s11912-011-0193-9 · Cited by 43 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors
Sha, D., Jin, Z., Budczies, J., Kluck, K., Stenzinger, A., & Sinicrope, F. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0522 · Cited by 859 · see citing works
Current advancements and future perspectives of immunotherapy in colorectal cancer research
Kishore, C., & Bhadra, P. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173819 · Cited by 126 · see citing works
Wang, P., Chen, Y., & Wang, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.672677 · Cited by 122 · see citing works
Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection
Galant, N., Krawczyk, P. A., Monist, M. J., Obara, A., Gajek, Ł., Grenda, A., Nicoś, M., Kalinka‐Warzocha, E., & Milanowski, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115893 · Cited by 111 · see citing works
Xu, L., Vacher, S., Boulai, A., Bernard, V., Baulande, S., Bohec, M., Bièche, I., Lerebours, F., & Callens, C. (2018) · Breast Cancer Research · doi:10.1186/s13058-018-1007-x · Cited by 81 · see citing works
Kim, J. E., Chun, S., Hong, Y. S., Kim, K., Kim, S. Y., Kim, J., Sung, C. O., Cho, E. J., Kim, T. W., & Jang, S. J. (2018) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2018.09.005 · Cited by 76 · see citing works
Borelli, B., Antoniotti, C., Carullo, M., Germani, M. M., Conca, V., & Masi, G. (2022) · Cancers · doi:10.3390/cancers14204974 · Cited by 62 · see citing works
Wiesweg, M., Kasper, S., Worm, K., Herold, T., Reis, H., Sara, L., Metzenmacher, M., Abendroth, A., Darwiche, K., Aigner, C., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0634-0 · Cited by 57 · see citing works
Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma
Bhangoo, M. S., Boasberg, P. D., Mehta, P., Elvin, J. A., Ali, S. M., Wu, W., & Klempner, S. J. (2018) · The Oncologist · doi:10.1634/theoncologist.2017-0342 · Cited by 50 · see citing works
Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
Medullary Pancreatic Carcinoma Due to Somatic POLE Mutation
Kryklyva, V., ter Linden, E., Kroeze, L. I., de Voer, R. M., Kolk, B., Stommel, M. W. J., Hermans, J. J., Luchini, C., Wood, L. D., Hruban, R. H., et al. (2020) · Pancreas · doi:10.1097/mpa.0000000000001588 · Cited by 26 · see citing works
Polymerase Epsilon-Associated Ultramutagenesis in Cancer
Xing, X., Jin, N. Y., & Wang, J. (2022) · Cancers · doi:10.3390/cancers14061467 · Cited by 24 · see citing works
Progress of Immune Checkpoint Inhibitors Therapy for pMMR/MSS Metastatic Colorectal Cancer
Qu, F., Wu, S., & Yu, W. (2024) · OncoTargets and Therapy · doi:10.2147/ott.s500281 · Cited by 20 · see citing works
Zhu, M., Cui, H., Zhang, L., Zhao, K., Jia, X., & Jin, H. (2021) · Translational Cancer Research · doi:10.21037/tcr-21-1601 · Cited by 19 · see citing works
Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer
Maletzki, C., Wiegele, L., Nassar, I., Stenzel, J., & Junghanß, C. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0476-x · Cited by 19 · see citing works
Queiroz, M. M., Lima, N. F., & Castria, T. B. D. (2023) · Cancers · doi:10.3390/cancers15071970 · Cited by 17 · see citing works
Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes
Zhu, Q., Zhang, J., Chen, Y., Hu, Q., Shen, H., Huang, R., Liu, Q., Kaur, J., Long, M. D., Battaglia, S., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32545 · Cited by 15 · see citing works
Gerber, T. S., Agaimy, A., Hartmann, A., Habekost, M., Roth, W., Stenzinger, A., Schirmacher, P., & Straub, B. K. (2021) · Diagnostic Pathology · doi:10.1186/s13000-021-01112-4 · Cited by 13 · see citing works
Jaballah-Gabteni, A., Tounsi, H., Kabbage, M., Hamdi, Y., Elouej, S., Ayed, I. B., Medhioub, M., Mahmoudi, M., Dallali, H., Yaïche, H., et al. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1961-9 · Cited by 12 · see citing works
Measuring Tumor Mutational Burden Using Whole-Exome Sequencing
Vilimas, T. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9773-2_3 · Cited by 10 · see citing works
POLE-mutated endometrial cancer: new perspectives on the horizon?
Fanale, D., Corsini, L. R., Piraino, P., Pedone, E., Brando, C., Russo, T. D. B., Ferraro, P. M., Simone, A., Contino, S., Prestifilippo, O., et al. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1633260 · Cited by 9 · see citing works
Monsur, M., Yamaguchi, M., Tashiro, H., Yoshinobu, K., Saito, F., Erdenebaatar, C., Li, C., Iwagoi, Y., Ohba, T., Iyama, K., et al. (2021) · Medical Molecular Morphology · doi:10.1007/s00795-020-00273-3 · Cited by 8 · see citing works
Cui, J., Chen, X., Zhai, Q., Chen, N., Li, X., Zhang, Y., Wang, H., Bian, X., Gao, N., Chen, D., et al. (2023) · Diagnostic Pathology · doi:10.1186/s13000-023-01287-y · Cited by 8 · see citing works
Hu, X., Guo, J., Shi, J., Li, D., Li, X., & Zhao, W. (2023) · BMC Pulmonary Medicine · doi:10.1186/s12890-023-02512-6 · Cited by 8 · see citing works
Maletzki, C., Hühns, M., Bauer, I., Prall, F., Junghanß, C., & Henze, L. (2019) · The Oncologist · doi:10.1634/theoncologist.2018-0614 · Cited by 3 · see citing works
Xu, T., Zhang, X., Wang, Z., Shen, L., Wang, X., & Li, J. (2026) · BMC Medicine · doi:10.1186/s12916-025-04611-z · Cited by 2 · see citing works
Ruprecht, N. A., Singhal, S., Schaefer, K., Gill, J. S., Bansal, B., Sens, D. A., & Singhal, S. K. (2023) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1161124 · Cited by 2 · see citing works
Westenend, P. J., & Dinjens, W. N. M. (2018) · Human Pathology · doi:10.1016/j.humpath.2018.01.028
Fan, Y., Liang, D., Zou, J., Kuang, W., Tong, L., Wang, C., Liu, T., Wang, W. T., & Feng, M. (2025) · Research Square · doi:10.21203/rs.3.rs-6689956/v1
Gerber, T. S., Agaimy, A., Hartmann, A., Habekost, M., Roth, W., Stenzinger, A., Schirmacher, P., & Straub, B. K. (2021) · Figshare · doi:10.6084/m9.figshare.14775726
Hu, X., Guo, J., Shi, J., Li, D., Li, X., & Zhao, W. (2023) · Figshare · doi:10.6084/m9.figshare.23564760
Diagnosis of Endometrial Carcinoma
Hussain, N., Gahine, R., Chandrakar, J., Jain, S., & Hussain, R. (2026) · Obstetrics and gynecology. · doi:10.5772/intechopen.1012666
Kang, J., Lim, D. M., Kim, Y., Shim, H., Kim, T., Park, K. J., Kang, S., Yu, C. S., Lee, J. L., Yu, Y., et al. (2026) · MedComm · doi:10.1002/mco2.70584
Biología molecular del cáncer colorrectal
García‐Foncillas, J., Jiménez, P., Ávila-Rodríguez, V., Macías, S. I. G., Manrique, M. E., Rendón-Hernández, J., Angarita, J. M., Calvo, J. F., & Bonilla, C. E. (2026) · Revista Colombiana de Hematología y Oncología · doi:10.51643/22562915.853
- Authors
- Castellucci, E., He, T., Goldstein, D. Y., Halmos, B., & Chuy, J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Department of Medical Oncology Montefiore Medical Center, Albert Einstein College of Medicine a , Bronx, New York, USA
- Corresponding author
- Chuy, Jennifer
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-05-01
- Volume
- 22
- Issue
- 5
- Pages
- 497-502
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC5423519
- OpenAlex
- W2611939233
- Cited by
- 34
- References
- 22
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 5
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Oncologist (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- DNA polymerase epsilon, POLE mutation, microsatellite stable, DNA repair deficiency, proofreading exonuclease, metastatic colorectal cancer, endometrial cancer, tumor genomic profiling, mutation rate
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, DNA Polymerase II, DNA Repair, Genotype, Humans, Male, Middle Aged, Neoplasm Metastasis, Phenotype, Prognosis, Colorectal Neoplasms, Germ-Line Mutation, Microsatellite Instability
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