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

Abstract

<div>Abstract<p><i>POLE</i> 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 <i>POLE</i> mutations that are not classified as drivers (<i>POLE</i> Variant) contribute to mutagenesis, we assessed TMB in 447 <i>POLE</i>-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 “<i>POLE</i> ExoD driver plus <i>POLE</i> Variant” (colorectal cancer and endometrial cancer, <i>P</i> < 0.001; ovarian cancer, <i>P</i> < 0.05). TMB increased with additional <i>POLE</i> variants (<i>P</i> < 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 “<i>POLE</i> ExoD driver plus <i>POLE</i> Variant” tumors. Overall, this study reveals a novel correlation between <i>POLE</i> variants in <i>POLE</i> 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.</p>Significance:<p>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 ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.</p></div>