Biology subjects

Kentepozidou, E.

Publications and source records attributed to Kentepozidou, E..

4 recordsLinked to original sources

bioRxiv2025

Germline and somatic variation influence nuclear-mitochondrial crosstalk in tumourigenesis

Hepatocellular carcinoma is the most prevalent primary liver cancer and arises from hepatocytes, which are very metabolically active and contain abundant mitochondria. Despite extensive characterisation of nuclear driver genes and pathways, the role of crosstalk between the mitochondrial and nuclear genomes in mitochondrial mutagenesis remains poorly understood. To address this, we leveraged a chemical carcinogenesis model of liver cancer in four mouse strains. We analysed hundreds of tumours with paired whole-genome sequencing and total RNA sequencing to comprehensively characterise mitochondrial mutations and expression. Following de novo assembly of strain-specific mitochondrial genomes, we devised an accurate and efficient heteroplasmy detection approach and analysed mitochondrial DNA (mtDNA) content and transcription. Across strains, there was high concordance of the number of heteroplasmies, mutation signatures, and variant allele frequencies. In contrast, the heteroplasmy rate and genic locations differed between strains, suggesting strain-specificity in DNA repair mechanisms in early tumour development. Independent of age or environmental factors, tumours had lower mtDNA content than adjacent normal liver, suggesting mitochondrial loss during tumourigenesis. Additionally, within individual strains, mtDNA content differences were associated with nuclear driver gene choice. Our comprehensive characterisation of mitochondrial genomes and expression patterns demonstrates that both germline and somatic genetic variation influence tumour mtDNA content, mutation patterns, and gene expression.

cancer biology↗

bioRxiv2025

Genetic background sets the trajectory of cancer evolution

Human cancers are heterogeneous. Their genomes evolve from genetically diverse germlines in complex and dynamic environments, including exposure to potential carcinogens. This heterogeneity of humans, our environmental exposures, and subsequent tumours makes it challenging to understand the extent to which cancer evolution is predictable. Addressing this limitation, we re-ran early tumour evolution hundreds of times in diverse, inbred mouse strains, capturing genetic variation comparable to and beyond that found in human populations. The sex, environment, and carcinogenic exposures were all controlled and tumours comprehensively profiled with whole genome and transcriptome sequencing. Within a strain, there was a high degree of consistency in the mutational landscape, a limited range of driver mutations, and all strains converged on the acquisition of a MAPK activating mutation with similar transcriptional disruption of that pathway. Despite these similarities in the phenotypic state of tumours, different strains took markedly divergent paths to reach that state. This included pronounced biases in the precise driver mutations, the strain specific occurrence of whole genome duplication, and differences in subclonal selection that reflected both cancer susceptibility and tumour growth rate. These results show that interactions between the germline genome and the environment are highly deterministic for the trajectory of tumour genome evolution, and even modest genetic divergence can substantially alter selection pressures during cancer development, influencing both cancer risk and the biology of the tumour that develops.

genomics↗

bioRxiv2019

Pervasive lesion segregation shapes cancer genome evolution

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion1, 2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can generate multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

cancer biology↗

bioRxiv2019

Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains

CTCF binding contributes to the establishment of higher order genome structure by demarcating the boundaries of large-scale topologically associating domains (TADs). We have carried out an experimental and computational study that exploits the natural genetic variation across five closely related species to assess how CTCF binding patterns stably fixed by evolution in each species contribute to the establishment and evolutionary dynamics of TAD boundaries. We performed CTCF ChIP-seq in multiple mouse species to create genome-wide binding profiles and associated them with TAD boundaries. Our analyses reveal that CTCF binding is maintained at TAD boundaries by an equilibrium of selective constraints and dynamic evolutionary processes. Regardless of their conservation across species, CTCF binding sites at TAD boundaries are subject to stronger sequence and functional constraints compared to other CTCF sites. TAD boundaries frequently harbor rapidly evolving clusters containing both evolutionary old and young CTCF sites as a result of repeated acquisition of new species-specific sites close to conserved ones. The overwhelming majority of clustered CTCF sites colocalize with cohesin and are significantly closer to gene transcription start sites than nonclustered CTCF sites, suggesting that CTCF clusters particularly contribute to cohesin stabilization and transcriptional regulation. Overall, CTCF site clusters are an apparently important feature of CTCF binding evolution that are critical the functional stability of higher order chromatin structure.

genomics↗