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REVIEW article
Front. Oncol.
Sec. Gynecological Oncology
Volume 14 - 2024 |
doi: 10.3389/fonc.2024.1369189
The game-changing impact of POLE mutations in Oncology -a review from a Gynecologic Oncology perspective
Provisionally accepted- Innsbruck Medical University, Innsbruck, Austria
Somatic mutations within the exonuclease proofreading domain (EDM) of the DNA polymerase Pol ε (POLE) gene are increasingly being discovered in ovarian, colorectal, urological and especially endometrial carcinoma (EC), where these are found in up to 10% of the cases. In EC there are five confirmed pathogenic somatic POLE-EDM mutations that are located at codons 286, 411, 297, 456 and 459, and these are called 'hotspot' mutations. POLE mutant tumors are ultramutated entities with a frequency of base substitution mutations that is among the highest in human tumors. Interestingly, these mutations are associated with excellent clinical outcome in EC. An additional six 'non-hotspot' POLE-EDM EC mutations are also considered pathogenic and they also confer a favorable prognosis. Currently, de-escalation of adjuvant treatment is recommended for EC patients with stage I-II tumors involving any of these 11 EDM mutations, even in patients with other clinicopathological risk factors. The high tumor mutational burden and the consequent increased infiltration of immune cells due to the overexpression of different neoantigens is probably responsible for the improved prognosis.Ongoing studies are examining POLE hotspot mutations among many non-gynecologic tumors, although the impact of such mutations on clinical outcomes is still a topic of debate.Therapeutic modalities for these hypermutated tumors are also an important consideration, including the need for or de-escalation of adjuvant treatments, and the response to immune therapy.This review addresses the critical role of POLE mutations in gynecologic oncology and oncology in general, focusing on definitions, variants, underlying pathogenic mechanisms, upcoming developments in the field and the clinic behavior associated with such mutations.
Keywords: POLE mutations, EDM, ultramutation, Tumor mutational burden, hotspot mutations, endometrial cancer
Received: 11 Jan 2024; Accepted: 31 Jul 2024.
Copyright: © 2024 Kögl, Pan, Marth and Zeimet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Alain G. Zeimet, Innsbruck Medical University, Innsbruck, Austria
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Teresa L. Pan