Large-Scale Study Maps DNA Damage Signatures Across Multiple Cancers

Clinicians struggle to match patients to therapies when genomic drivers and repair defects are incompletely characterized across tumor types. Comprehensive, whole-genome views of mutational processes remain limited in routine practice. Researchers now report a large-scale analysis that maps DNA damage signatures across multiple cancers.

The University of Manchester and The Institute of Cancer Research, London, analyzed whole-genome sequencing data from nearly 11,000 National Health Service (NHS) patients as part of Genomics England’s 100,000 Genomes Project, described as the largest single cancer genomics study undertaken worldwide. Across 16 cancers, investigators examined hundreds of millions of somatic alterations spanning the full three‑billion‑base human genome. The work, conducted over six years, produced what is described as the most comprehensive map to date of the genetic “scars” left by oncogenic processes.

The analysis cataloged 370 million mutations and assigned them to 134 distinct mutational signatures, defined as patterns of DNA damage that act like fingerprints of the processes that caused the cancer. Of these, 26 signatures were not previously included in commonly used reference databases. Beyond single‑base substitutions, the study also assessed more complex, multi‑base genomic changes across the entire genome.

A key finding was broad evidence of homologous recombination deficiency (HRD), a DNA repair weakness linked to sensitivity to poly(ADP‑ribose) polymerase (PARP) inhibitors and platinum‑based chemotherapy. HRD signatures were identified in 16% of breast tumors and 14% of ovarian tumors. Based on these data, the authors estimate that more than 7,700 breast cancer patients and over 1,000 ovarian cancer patients in the United Kingdom could benefit from HRD-targeted therapies, a substantially higher number than currently identified through standard genetic testing focused on BRCA1 and BRCA2 mutations.

The study also adds to growing evidence that toxins produced by certain Escherichia coli strains may play a role in early-onset bowel cancer. This mutational signature was found more frequently in younger patients than in older individuals, suggesting a potential age-related exposure or susceptibility factor.

Findings are published in Nature Genetics. The work was co‑led by teams at The University of Manchester and The Institute of Cancer Research, London, in collaboration with Genomics England and the NHS. The authors state that the results could increase the number of cancer patients recognized as candidates for targeted and immune‑based treatments.

“Every cancer develops because DNA is damaged over time. Different causes such as ultraviolet light, tobacco smoke or inherited gene faults leave different patterns in the genome. By reading these patterns we can now understand, in a larger proportion of cancers, what caused the cancer, when key mutations occurred, and which treatments are most likely to work,” said David Wedge, professor of cancer genomics and data science at The University of Manchester.

“The scale of this study was very large, as we analyzed samples from almost every tumor type. The quantity of data was enormous, and although laborious to work through, we have been rewarded with a very exciting outcome. This study provides one of the clearest demonstrations yet that reading the full genetic history of a tumor can unlock clues to better patient care. The future of cancer treatment lies not just in finding mutations, but in understanding the story they tell,” said Richard Houlston, head of cancer genomics at The Institute of Cancer Research.

Related Links
The Institute of Cancer Research, London
The University of Manchester