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

Autor:	Shah SM; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; Science Scholars Program, Temple University, Philadelphia, Pennsylvania., Demidova EV; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation., Ringenbach S; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; Lewis Katz School of Medicine, Temple University, Bethlehem, Pennsylvania., Faezov B; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation.; Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Andrake M; Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Gandhi A; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; University College Dublin School of Medicine and Medical Science, Dublin, Ireland., Mur P; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain., Viana-Errasti J; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain., Xiu J; Caris Life Sciences, Phoenix, Arizona., Swensen J; Caris Life Sciences, Phoenix, Arizona., Valle L; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain., Dunbrack RL Jr; Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Hall MJ; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Arora S; Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.; Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Jan 26; Vol. 4 (1), pp. 213-225. Date of Electronic Publication: 2024 Jan 08.
DOI:	10.1158/2767-9764.CRC-23-0312
Abstrakt:	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 TMB in 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 ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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