Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity - Abstract

Q: What are the main findings regarding TMB levels?

Tumors with “POLE ExoD driver plus POLE Variant” show significantly higher TMB, and TMB increases with additional POLE variants but plateaus at 2, consistent with an association between these variants and elevated TMB.

Sep 21, 2026

Uploaded by Logic

POLE driver mutations in the exonuclease domain (ExoD driver) are common across cancers, producing extremely high tumor mutation burden (TMB). This study evaluates whether non-driver POLE variants (POLE Variant) contribute to mutagenesis by analyzing TMB in 447 POLE-mutated colorectal, endometrial, and ovarian tumors. TMB is highest in tumors carrying “POLE ExoD driver plus POLE Variant” and increases with additional variants before plateauing at 2. Integrated AlphaFold2 POLE modeling links multiple variants to altered POLE functionality and higher immunogenic neoepitope prevalence, suggesting a modifier role requiring functional validation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Study design and patient/tumor cohorts

Key findings on TMB and neoepitopes

Clinical implications and limitations

Significance

Introduction

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-23-0312](https://doi.org/10.1158/2767-9764.CRC-23-0312) Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity Shreya M. Shah1 , 2 , Elena V. Demidova1 , 3 , Salena Ringenbach1 , 4 , Bulat Faezov3 , 5 , Mark Andrake5 , Arjun Gandhi1 , 6 , Pilar Mur7 , Julen Viana-Errasti7 , Joanne Xiu8 , Jeffrey Swensen8 , Laura Valle7 , Roland L. Dunbrack Jr5 , Michael J. Hall1 , 9 , and Sanjeevani Arora1 , 10 OPEN ACCESS Check for updates ABSTRACT POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB) . To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMBin 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high ≥10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with “POLE ExoD driver plus POLE Variant” (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05) . TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the “POLE ExoD driver plus POLE Variant” tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. Significance: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultrahigh TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes. Introduction DNA polymerase epsilon (POLE) is an essential mediator of accurate DNA replication, based in part on its roles in DNA synthesis and DNA proofreading (1) . POLE mutations that impair DNA proofreading lead to increased mutagenesis, and in the germline confer an increased risk of colorectal, endometrial, and other cancers (2–9) . Somatic POLE mutations affecting proofreading are relatively rare, typically observed in approximately 2%–8% of colorectal cancers and approximately 7%–15% of endometrial cancers, and less commonly in other tumors (3) . Tumors harboring POLE mutations that lead to 1 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 2 Science Scholars Program, Temple University, Philadelphia, Pennsylvania. 3 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation. 4 Lewis Katz School of Medicine, Temple University, Bethlehem, Pennsylvania. 5 Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 6 University College Dublin School of Medicine and Medical Science, Dublin, Ireland. 7 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 8 Caris Life Sciences, Phoenix, Arizona. 9 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. proofreading defects are typically ultra-hypermutated [>100 mutations/Mb (mut/Mb)] and have a specific context of mutational signatures (COSMIC signatures 10a and 10b; ref. 10) . The in

FAQs

What question does the study address about POLE mutations?

It tests whether POLE mutations not classified as drivers (POLE Variant) also contribute to mutagenesis in cancers that already carry POLE exonuclease-domain (ExoD) driver mutations.

How did the researchers evaluate the relationship between POLE variants and TMB?

They assessed TMB in 447 POLE-mutated colorectal, endometrial, and ovarian cancers stratified as TMB-high (≥10 mut/Mb) or TMB-low (<10 mut/Mb), and examined changes across different combinations of ExoD drivers and variants.

What are the main findings regarding TMB levels?

Tumors with “POLE ExoD driver plus POLE Variant” show significantly higher TMB, and TMB increases with additional POLE variants but plateaus at 2, consistent with an association between these variants and elevated TMB.

Sep 21, 2026

Uploaded by Logic