Biology subjects

Rayner, T. F.

Publications and source records attributed to Rayner, T. F..

3 recordsLinked to original sources

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↗

bioRxiv2018

Mutational landscape of a chemically-induced mouse model of liver cancer

Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and have a critical role in validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the spectra of genomic alterations driving these mouse tumour genomes are comparable to those found in humans. Here, we provide a detailed characterisation of the exome-wide pattern of mutations in tumours from mice exposed to diethylnitrosamine (DEN), a commonly used model of hepatocellular carcinoma (HCC). DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with very few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/{beta}-catenin signalling in cancer progression. Conclusion: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly-used carcinogen model of hepatocellular carcinoma, facilitating the future use of this model to understand the human disease.

cancer biology↗