Improved DNA Sequencing Tool Uncovers Hidden Mutations Driving Cancer

Detecting these rare mutations in normal tissues has long been difficult, as standard sequencing tools cannot distinguish true genetic changes from technical errors. Now, a newly refined DNA sequencing technique provides an unprecedented view of how tissues mutate over time, offering insights into the earliest stages of cancer development.

The research, led by the Wellcome Trust Sanger Institute (Cambridgeshire, UK) in collaboration with the TwinsUK study at King’s College London (London, UK), introduces an enhanced version of nanorate sequencing (NanoSeq)—an ultra-accurate tool for detecting somatic mutations. This improved version can precisely measure mutation rates and patterns while identifying driver mutations across various tissues. By combining high-resolution sequencing with targeted sampling, it reveals even the rarest genetic alterations in healthy cells.

In the largest study of its kind, the researchers applied targeted NanoSeq to cheek swabs and blood samples from more than 1,000 volunteers aged 21 to 91. The analysis uncovered over 340,000 mutations in cheek cells, including more than 62,000 mutations in known cancer driver genes, with 49 genes under positive selection. The results, published in Nature, showed distinct mutational signatures linked to ageing, smoking, and alcohol consumption, highlighting how lifestyle factors shape genetic risk.

The findings suggest that while somatic mutations are widespread, most mutated clones remain small and do not progress to cancer, providing reassurance about the body’s natural control mechanisms. The study’s scale and precision also demonstrate the potential of NanoSeq to measure how environmental and inherited factors influence DNA stability. The researchers aim to use this technology in future population-wide studies and cancer prevention efforts by identifying mutagenic exposures before disease develops.

“With NanoSeq, we are able to measure the genetic consequences of certain lifestyle factors in normal tissues, meaning we can better understand why and how they cause cancer,” said Dr. Iñigo Martincorena, Senior Author at the Wellcome Sanger Institute. “We hope that this new ability to study somatic mutations in non-invasive tissue biopsies from healthy individuals becomes a useful tool for cancer prevention, by improving our ability to identify exposures in the population that could be mutagenic and carcinogenic, and by helping in the discovery of cancer preventive drugs.”

Related Links:
Wellcome Trust Sanger Institute
King’s College London