One of the most interesting aspects of precision medicine is that in order to treat each person’s disease individually, we have to understand how the disease looks across a population. In other words, to achieve precision — down to the impact of single mutations — we have to think big. Really big. This is best accomplished by looking at thousands of whole cancer genomes, as was undertaken in a recent breakthrough study published in Science, Substitution mutational signatures in whole-genome-sequenced cancers in the UK population.
The study is groundbreaking for the field. According to an article in GEN, first author Andrea Degasperi, PhD, a research associate at the University of Cambridge, said, “Whole-genome sequencing gives us a total picture of all the mutations that have contributed to each person’s cancer. With thousands of mutations per cancer, we have unprecedented power to look for commonalities and differences across NHS patients, and in doing so we uncovered 58 new mutational signatures and broadened our knowledge of cancer.”
The study validates Personalis’ mission and approach, as well. It confirms our decision to use a whole-genome sequencing (WGS) approach in our NeXT PersonalTM platform. In support of the superiority of a whole-genome approach, the authors noted that “[t]he power to accurately discern mutational signatures with a pure WGS dataset is orders of magnitude greater than that obtained by means of other sequencing strategies. The genomic footprint for whole-exome sequencing (WES) is 100-fold lower and is 2000- to 4000-fold lower in targeted sequencing (TS) experiments.”
The new signatures discovered demonstrate there is more to be learned about the origins of cancer, how it changes over time and what treatment options could be most effective, particularly for rare mutation signatures found only in a fraction of the population. In fact, as the authors note, “an agnostic WGS approach to tumor characterization will help reveal abnormalities that we currently neither seek nor detect using customary diagnostic pathways.”
As reported in an article by the University of Cambridge, “The reason it is important to identify mutational signatures is because they are like fingerprints at a crime scene — they help to pinpoint cancer culprits,” said Serena Nik-Zainal, from the Department of Medical Genets and an honorary consultant in clinical genetics at CUH. “Some mutational signatures have clinical or treatment implications — they can highlight abnormalities that may be targeted with specific drugs or may indicate a potential ‘Achilles’ heel’ in individual cancers.”
For further reading, here is a curated a list of news highlighting this groundbreaking study: