Scientists have detected 58 new possible causes of cancer: what are “mutational signatures”?

Globally, it is estimated that in 2020 there were 19.3 million new cases of cancer (18.1) and nearly 10.0 million deaths from the disease (9.9 million all data not including non-melanoma skin cancer), according to data from the World Health Organization (WHO). While the pandemic was going through the world, scientists applied to the studies of this transversal ailment did not stop delving into possible ways to attack it in more effective ways. One of the milestones pursued is to provide precise guidance and reduce the negative impacts of ongoing treatments.

Genomic analysis, a task that is in its dawn and which continues to surprise daily with new possibilities, has now, thanks to the largest study of its kind, allowed a team of scientists led by Professor Serena Nik-Zainal from the Hospitals of the University of Cambridge (CUH) and the university itself, to analyze the complete genetic makeup or whole genome sequences (WGS) of more than 12,000 cancer patients from the NHS, the National Health Service of Great Britain.

Due to the large amount of data provided by whole-genome sequencing, researchers were able to detect patterns in cancer DNA, known as “mutational signatures”, that provide clues as to whether a patient has in the past been exposed to environmental causes of cancer such as smoking or ultraviolet light, or has internal cell failures. Professionals were also able to detect 58 new mutational signatures, suggesting that there are additional causes of cancer that we do not yet fully understand. The results have just been published in the specialized journal Science.

Genomic data was provided by the 100,000 Genomes Project, an English-wide clinical research initiative to sequence that number of whole genomes from around 85,000 patients affected by rare diseases or cancer. “WGS gave us a complete picture of all the mutations that have contributed to each person's cancer,” said the first author, Andrea Degasperi, from the Cambridge Department of Oncology. With thousands of cancer mutations, we have unprecedented power to look for similarities and differences among NHS patients, and in doing so, we discovered 58 new mutational signatures and expanded our knowledge of the disease.”

The reason why specialists report that it is important to identify mutational signatures is because they work like fingerprints at the crime scene: “they help identify the culprits of cancer,” adds Serena Nik, Zainal, from the Department of Medical Genetics and an honorary consultant in clinical genetics at CUH. Some mutational signatures have clinical or treatment implications: they are able to highlight abnormalities that can be treated with specific drugs or may indicate a possible Achilles heel in individual cancers. We were able to carry out a forensic analysis of more than 12,000 NHS cancer genomes thanks to the contribution of samples from patients and doctors from all over England. We have also created FitMS, a digital tool to help scientists and physicians identify old and new mutational signatures in cancer patients, to potentially inform cancer management more effectively.”

Dame Sue Hill, chief scientific officer for England and senior responsible for genomics at the NHS, stated in this regard that “the contribution of the NHS to the 100,000 Genomes Project was vital to this research and we have been able to demonstrate how data can transform the care we provide to patients, which is a cornerstone of the NHS Genomic Medicine Service”.

Nik-Zainal anticipates that genomic analysis will become a routine part of cancer screenings. Since the current standard of care often dictates that patients undergo a blood test or CT scan, it sees genomic testing as another step towards personalized care. “Today, some people think that genomics is a bit esoteric, mysterious or just for academia, but one of the things that Project 100,000 Genomes shows us is that we can recruit and perform cancer WGS at scale from a public sector service, and have an impact on the population of the real world,” he concluded.

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