AccScience Publishing / TD / Online First / DOI: 10.36922/td.3659
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ORIGINAL RESEARCH ARTICLE

Exploring somatic mutations in POLE and POLD1: Their role in colorectal cancer pathogenesis and potential therapeutic strategies

Hersh Abdul Ham-Karim1* ,  Narmeen Salih Ahmad2 ,  Mohammad Ilyas3,4
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1 Pharmacy department, College of Medicine, Komar University of Science and Technology, Sulaymaniyah, Iraq
2 Department Microbiology, Faculty Health and Biomedicine, Kurdistan Institution for Strategic Studies and Scientific Research, Sulaimani, Iraq
3 Nottingham Molecular Pathology Node, Faculty Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
4 Division of Cancer and Stem Cell, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
Tumor Discovery, 3659 https://doi.org/10.36922/td.3659
Submitted: 14 May 2024 | Accepted: 17 July 2024 | Published: 6 September 2024
(This article belongs to the Special Issue Colorectal Cancer: Best Tools for Diagnosis to Management Strategies)
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Colorectal cancer (CRC) is one of the major causes of morbidity and mortality worldwide, resulting from the accumulation of genetic and epigenetic alterations in several oncogenes and tumor suppressor genes. Recent studies have identified germline and somatic mutations in the exonuclease domain regions of both epsilon polymerase (POLE) and delta polymerase (POLD1) genes in CRCs. We sought to examine the mutation of these genes in a series of sporadic CRCs. To do this, we extracted DNA from 100 primary CRC samples and 40 corresponding normal tissue samples, which had been previously characterized for clinicopathological and molecular features. We employed a combination of quick-multiplex consensus (QMC)-polymerase chain reaction (PCR) and co-amplification at lower denaturation temperature (COLD)-PCR, followed by high-resolution melting (HRM) analysis and Sanger sequencing, to investigate the exonuclease domain regions of POLE and POLD1 genes for somatic mutations that may potentially alter the proofreading activities of these genes. In silico predictions of the functional significance of the identified genetic alterations were performed using the protein variation effect analyzer, sorting intolerant from tolerant, and PON-P2 algorithms. We identified a total of eight new and non-recurrent somatic variants in the endonuclease domains of POLE and two in POLD1. Nine out of ten variants caused amino acid substitutions, whereas one resulted in a stop codon. Although no significant associations or correlations were found between the POLE/POLD1 mutations and the clinicopathological or molecular features of the CRC cases, most of the POLE/POLD1-mutated cases were microsatellite stable (90%) and aneuploid (80%). Furthermore, in silico analyses showed that nine of the ten variants would likely cause some adverse effect on protein function. Ten somatic variants with predicted proofreading activity-altering effects have been identified in the endonuclease domains of POLE and POLD1 in CRC using a combination of QMC-PCR, COLD-PCR, HRM analyses, and Sanger sequencing.

Keywords
Colorectal cancer
Novel somatic mutations
POLE
POLD1
Funding
This work was funded by the University of Nottingham (for Mohammad Ilyas).
Conflict of interest
The authors declare no conflicts of interest.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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