Cancer causes: 58 new ‘mutational signatures’ offer insights

  • Cancer is usually a result of several thousand genetic mutations.
  • Finding these mutations can help doctors identify the causes of cancers and treat them appropriately.
  • Now, a study using whole-genome sequencing has found new mutational signatures that reveal clues to the causes of many cancers.
  • The researchers hope that this will lead to improvements in the diagnosis and treatment of cancer patients.

Cancer causes 1 in 6 deaths worldwide. Some risk factors are known, such as tobacco use, an unhealthy diet, or viruses such as HPV. But many cancers appear to develop spontaneously, without an obvious environmental risk factor. The “hunt” for the causes of cancer is a key area of medical research.

What is known is that cancer usually develops slowly, with a build-up of thousands of random mutations before a cell becomes malignant. A mutation is a change in DNA that may be spontaneous or caused by an external mutagenic agent, such as radiation, some chemicals, and some viruses.

Now, a new study in the United Kingdom has used whole genome sequencing in cancer patients to discover a large number of new mutational signatures — imprints of DNA damage and repair that occur during the formation of tumors — which may help researchers identify the causes of many cancers.

Dr. Santosh Kesari, director of neuro-oncology at Providence Saint John’s Health Center and chair of the Department of Translational Neurosciences and Neurotherapeutics at Saint John’s Cancer Institute in Santa Monica, CA, commented on the study for Medical News Today.

“This study follows on genomic research done over the past 2 decades and highlights that there is still yet more to learn about human health and disease by interrogating the human genome in ever more depth than previously done in cancer patients.”

– Dr. Kesari

Dr. Kesari, who was not involved in the research, is also the regional medical director for the Research Clinical Institute of Providence Southern California.

The new study appears in the journal Science.

Large cohort study

The researchers carried out DNA analysis of tumours from more than 11,000 cancer patients in the U.K. They collected the data via the 100,000 Genomes Project, a U. K. initiative that investigates the role of genes in health and disease.

Using whole-genome sequencing, the researchers performed mutational signature analysis on all the samples. The researchers then compared their findings with those from the International Cancer Genome Consortium (ICGC) and the Hartwig Medical Foundation (HMF) in the Netherlands. This allowed them to identify which mutational signatures had not been found before.

Previously unseen mutations

The team developed an algorithm — which they called Signature Fit Multi-Step (FitMS) — to identify rare mutational signatures. Together with many known, common mutational signatures in the tumors, they identified 58, previously undiscovered, mutational signatures. These provide clues about past exposure to environmental causes of cancer and internal cellular malfunctions.

Dr. Andrea Degasperi, research associate at the University of Cambridge and the first author of the study, commented: “Whole-genome sequencing gives us a total picture of all the mutations that have contributed to each person’s cancer.”

The 58 new mutational signatures they found suggest that there are additional causes of cancer that are not yet fully understood.

Dr. Kesari was impressed by the study, as he told MNT: “The study sequenced the whole genome (both the “silent” and expressed parts) rather than just the expressed parts which we have focused on in the past. This broader approach was able to identify 58 new although rare mutations and also identified fingerprints of damage due to exposures to external environmental toxins or to internal cancer mutations.”

Potential for new treatments

The authors suggest that the identification of these new mutational signatures may lead to new individualized cancer treatments.

Prof. Serena Nik-Zainal, Professor of Genomic Medicine and Bioinformatics, University of Cambridge, who led the study, explained:

“[M]utational signatures […] are like fingerprints at a crime scene — they help to pinpoint cancer culprits. Some mutational signatures have clinical or treatment implications — they can highlight abnormalities that may be targeted with specific drugs.”

– Prof. Nik-Zainal

Dr. Kesari agreed: “This study further expands our knowledge of cancer causes and how best to treat it with newer approaches such as personalized drugs based on mutations (targeted therapy) and stimulating the immune system to kill cancer (immunotherapy).”

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