Biology subjects

Zole, E.

Publications and source records attributed to Zole, E..

3 recordsLinked to original sources

bioRxiv2025

Functional Role of Small Extrachromosomal Circular DNA in Colorectal Cancer

Extrachromosomal circular DNA (eccDNA) are circular DNA molecules that originate from chromosomal DNA but exist independently. While large eccDNA (ecDNA) contributes to tumorigenesis, the role of smaller eccDNA (<100,000 base pairs) in cancer remains unclear. Our analysis of 25 colorectal cancer (CRC) tumors and adjacent non-tumorous tissues revealed that eccDNA is significantly more abundant in tumor tissues, correlating strongly with chromosomal amplifications. The presence of whole intact genes on 1.29% of eccDNA was non-random. We identified 84 genes that recurred across tumors of multiple patients when present on eccDNA with 19% of genes being cancer-associated. eccDNA-borne genes were often accompanied by increased expression, and their contribution to expression was much larger than that from linear amplifications and the larger ecDNA. The cytokine gene CXCL5 exemplified this phenomenon, showing substantial copy-number increase and upregulation when present on eccDNA. Functional validation in cell lines showed that CXCL5 eccDNA enhanced transcriptional output and immune cell recruitment function. The recurrence and overexpression of CRC-related genes on eccDNA indicate their selection in tumors, suggest eccDNA can serve as a novel mechanism for dynamically influencing gene expression and is capable of conferring cancer phenotypes to cells. Analysis of chromatin landscapes revealed that eccDNA preferentially forms at sites of open chromatin and active transcription, with architectural boundaries marked by CTCF protein. Clinically, patients with higher eccDNA levels showed poorer relapse-free survival. These findings suggest that circular DNA elements across the entire size spectrum participate in cancer evolution, positioning eccDNA as a potential therapeutic target and prognostic biomarker.

cancer biology↗

bioRxiv2024

Changes in TP53 gene, telomere length, mitochondrial DNA, and its amount in benign prostatic hyperplasia patients

Benign prostatic hyperplasia (BPH) is a growing issue due to an ageing population; however, there are not enough studies connecting it with ageing hallmarks. Some of the ageing hallmarks are changes in telomere length (TL) and genetic changes like possible mutations in the TP53 gene or mitochondrial genome (mtDNA). Our study investigated these factors to see if they could be linked with BPH. Prostate tissue samples were obtained from 32 patients with BPH (and 30 blood samples). As a healthy control group, age-matching blood DNA samples were used. For mtDNA sequence data comparison, 50 samples of a general Latvian population were used. The full mtDNA genome was sequenced using Next Generation Sequencing (NGS), for TP53 gene - Sanger sequencing, and for mtDNA amount and telomere length - qPCR assay. BPH patients in prostate tissue had much higher TL than in blood cells, and the healthy controls had the shortest telomeres. Also, the mtDNA amount in BPH prostate tissue was the highest compared with blood, and controls had the smallest amount. In the TP53 gene, we did not find any mutations that could be linked to BPH. In the mtDNA genome, we found several unique mutations and heteroplasmic changes, as well as changes that have been linked before with prostate cancer (PC). In conclusion, prolonged telomeres and changes in mtDNA amount might be involved in the development of BPH. Concerning mtDNA genome changes, some of the heteroplasmic or homoplasmic variants might contribute to the development of BPH. More studies should be conducted to prove or disapprove of these connections.

genetics↗

bioRxiv2024

Technical and biological variations in the purification of extrachromosomal circular DNA (eccDNA) and the finding of more eccDNA in the plasma of lung adenocarcinoma patients compared with healthy donors

Human plasma DNA originates from all tissues and organs, holding the potential as a versatile marker for diseases such as cancer, as fragments of cancer-specific alleles can be found circulating in the blood. While linear DNA has been studied intensely as a liquid biomarker, the role of circular circulating DNA in cancer is more unknown due, in part, to a lack of comprehensive testing methods. Our developed method profiles extrachromosomal circular DNA (eccDNA) in plasma, integrating Solid-Phase Reversible Immobilization (SPRI) bead purification, the removal of linear DNA and mitochondrial DNA, and DNA sequencing. As an initial assessment, we examined the method, biological variations, and technical variations using plasma samples from four patients with lung adenocarcinoma and four healthy and physically fit individuals. Despite the small sample group, we observed a significant eccDNA increase in cancer patients in two independent laboratories and that eccDNA covered up to 0.4 % of the genome/mL plasma. We found a subset of eccDNA from recurrent genes present in cancer samples but not in every control. In conclusion, our data reflect the large variation found in eccDNA sequence content and show that the variability observed among replicates in eccDNA stems from a biological source and can cause inconclusive findings for biomarkers. This suggests the need to explore other biological markers, such as epigenetic features on eccDNA.

molecular biology↗