Aberrant DNA methylation is an early hallmark of malignant transformation. We profiled the genome-wide methylation landscape of 480 pre-malignant and tumour specimens across six tissue types, identifying 1,284 differentially methylated regi…
A subpopulation of drug-tolerant persister cells underlies relapse after targeted therapy. We characterised persister states in lung adenocarcinoma using paired single-cell transcriptomic and chromatin-accessibility profiling across eight p…
Intratumoural heterogeneity shapes treatment response. We applied single-cell DNA and RNA sequencing to 36 colorectal tumours spanning disease stages, reconstructing clonal phylogenies at single-cell resolution. Branched evolution dominated…
Circulating tumour DNA enables non-invasive cancer detection. We developed a next-generation sequencing assay targeting methylation and mutation signals simultaneously, validated in a prospective cohort of 1,150 participants. The combined a…
The tumour suppressor p53 safeguards genome integrity. We modelled p53 loss in organoids and tracked the emergence of structural variation over 40 passages. p53 deficiency produced a rapid accumulation of chromothriptic events concentrated …
The tumour microenvironment is epigenetically remodelled during progression. We mapped methylation changes in stromal and immune compartments of breast tumours using sorted-population bisulfite sequencing. Cancer-associated fibroblasts acqu…
Synthetic lethality exploits tumour-specific dependencies. We performed genome-wide CRISPR screens in BRCA-mutant cancer lines to map DNA-repair vulnerabilities beyond PARP. Loss of POLQ and USP1 emerged as the strongest selective dependenc…
Mismatch-repair deficiency predicts immunotherapy benefit, but finer stratification is needed. We analysed DNA-repair signatures across 2,400 treated patients, deriving a composite repair-deficiency score. The score stratified response with…
Evasion of apoptosis is a core hallmark of cancer and a driver of therapy resistance. We dissected apoptotic priming in matched pre- and post-treatment biopsies using BH3 profiling. Resistant tumours showed reduced mitochondrial priming and…
Polygenic background modifies penetrance in hereditary cancer. We built a polygenic risk model in 18,000 carriers of high-penetrance variants across five syndromes. Polygenic score shifted lifetime risk by up to 31 percentage points within …
Telomere attrition precipitates a state of chromosomal instability that fuels tumour heterogeneity. We characterised telomere dynamics across 312 aggressive carcinomas using long-read sequencing. Tumours with critically short telomeres show…
KRAS-mutant cancers remain difficult to treat. We performed genome-wide CRISPR knockout screens across 28 KRAS-mutant tumour models to map synthetic-lethal interactions. Dependencies clustered by tissue of origin rather than KRAS allele, an…
