Biology subjects

Liver Cancer Evolution Consortium,

Publications and source records attributed to Liver Cancer Evolution Consortium,.

3 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↗

bioRxiv2022

Strand-resolved mutagenicity of DNA damage and repair

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here, we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small DNA adducts, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky adducts5. We find that DNA damage tolerance is also common during transcription, where RNA-polymerases frequently bypass lesions without triggering repair. At multiple genomic scales, we show the pattern of DNA damage induced mutations is largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can corrupt the fidelity of nucleotide excision repair and actively drive oncogenic mutagenesis. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage, thereby shaping cancer genome evolution.

genomics↗