This issue gathers work on the genomic and epigenomic drivers of carcinogenesis, from the mechanisms that let a cell escape its constraints to the computational methods that let us watch them do it. Original research sits alongside methodological papers, and every article is free to read from the day it appears.
The issue is organised around three threads. Discovery covers tumour evolution, epigenetic regulation and structural variation, including single-cell and spatial approaches to heterogeneity. Translation takes in biomarkers, liquid biopsy and mechanisms of acquired treatment resistance. Methods covers benchmarking studies and analytical tooling released with documented, runnable code.
All articles are published under a Creative Commons licence with no article processing charges. Data and code are deposited as a condition of acceptance, so every figure in this issue can be reproduced from its source.
Eleanor Whitfield, Hiroshi Sato
Pages 1-12
Abstract
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 regions that separate pre-malignant from invasive disease. Hypermethylation of…
Marcus Bennett
Pages 13-24
Abstract
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 patient-derived models. Persisters converged on a shared quiescent programme…
Aisha Rahman
Pages 25-38
Abstract
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 in mismatch-repair-proficient tumours, while deficient tumours showed…
David Okonkwo
Pages 39-51
Abstract
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 assay achieved 84% sensitivity at 99.4% specificity for stage I-II disease…
Sofia Lindqvist
Pages 52-64
Abstract
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 on chromosomes 8 and 17, accompanied by whole-genome doubling in a third of…
Ingrid Moreau
Pages 65-77
Abstract
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 acquired a distinct hypomethylated enhancer landscape driving chemokine secretion…
Elena Petrova
Pages 78-91
Abstract
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 dependencies, and combined inhibition overcame acquired PARP-inhibitor resistance in…
Yuki Tanaka
Pages 92-104
Abstract
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 within microsatellite-instability-high tumours and identified a responsive subgroup…
Carlos Mendez
Pages 105-118
Abstract
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 a shift in dependence from BCL-2 to MCL-1, which BH3-mimetic combination…
Lena Hoffmann
Pages 119-132
Abstract
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 the same monogenic genotype, with the largest effect in Lynch syndrome…
Yuki Tanaka, Laura Esposito
Pages 133-146
Abstract
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 showed a fivefold excess of fusion-bridge-breakage events, and telomerase…
Priya Nair
Pages 147-160
Abstract
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, and SHOC2 loss was selectively lethal across pancreatic models irrespective of…