The stability of the human genome depends upon a delicate balance between replication by high- and low-fidelity DNA polymerases. Aberrant replication by error-prone polymerases or loss of function of high-fidelity polymerases predisposes to genetic instability and, in turn, cancer. DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is responsible for the majority of leading strand synthesis, and mutations in Pol ε have been increasingly associated with various human malignancies. The clinical significance of Pol ε mutations, including how and whether they should influence management decisions, remains poorly understood. In this report, we describe a 24-year-old man with an aggressive stage IV high-grade, poorly differentiated colon carcinoma who experienced a dramatic response to single-agent checkpoint inhibitor immunotherapy after rapidly progressing on standard chemotherapy. His response was complete and durable and has been maintained for more than 48 months. Genetic testing revealed a P286R mutation in the endonuclease domain of POLE and an elevated tumor mutational burden of 126 mutations per megabase, both of which have been previously associated with response to immunotherapy. Interestingly, tumor staining for PD-L1 was negative. This case study highlights the importance of genetic profiling of both early and late-stage cancers, the clinical significance of POLE mutations, and how the interplay between genetic instability and immune-checkpoint blockade can impact clinical decision-making.
Submitted August 21, 2021; final revision received November 17, 2021; accepted for publication November 18, 2021.
Michael L. Durando, MD, PhD, and Sanjay V. Menghani, PhD, contributed equally to this study.
Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: Dr. Durando’s training was supported by the Training Program in Immunobiology of Normal and Neoplastic Lymphocytes funded by the NCI of the NIH under award number T32-CA-009140. Dr. Menghani’s training was supported by the National Institute of General Medical Sciences of the NIH under award number 1F30GM139246-01A1.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.