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Insights from Largest-Ever Tumour Genome Analysis Ready for Clinical Use

Written by Charlotte Harrison, Science Writer 

A study headed by Cambridge University scientists has conducted the largest whole-genome sequencing analysis of tumours to date. The research — published in Science —  provides a treasure trove of insights into the underlying molecular mechanisms behind different cancer types and has identified novel mutational signatures that could soon impact patient care. 

Large numbers and new signatures 

The study examined a cohort of over 15,000 whole-genome–sequenced cancers from patients recruited from UK NHS Genomic Medicine Centres. Many tumour types, such as lung, kidney, breast, and bone and soft-tissue cancers, had thousands of samples.   

First, the authors hunted for organ-specific mutational signatures. During tumour development, mutations accumulate in the genome; the specific pattern of these mutations makes up the mutational signature. The researchers identified 82 single-base substitution signatures and 27 double-base substation signatures. By comparing their data to other cancer genetics projects, they confirmed several signatures that are already known, but also uncovered 58 new ones.  

Of note, the study revealed rare mutational patterns that could not have been picked out from smaller data sets.  

The authors then tried to elucidate the biology that underlies the signature wherever possible.  Many signatures showed evidence of expected mutagenic processes, including effects of cellular metabolism, deficiencies of DNA repair, and environmental sources. Some signatures could be linked to mechanisms through association with driver gene mutations. Yet the mechanism behind many signatures could not be determined, suggesting that there are additional causes of cancer that we don’t yet fully understand.  

Ready for clinical action 

To ensure that the wealth of genetic data from this research can be translated to patient care and treatment, the researchers developed a computer tool called Signature Fit Multi-Step (FitMS) to help clinicians identify mutational signatures – both known and novel. FitMS first detects common, organ-specific signatures, then determines whether an additional rare signature is also present in a patient’s tumour. 

This computer tool could have an immediate clinical impact. “FitMS is ready-to-use…we are hoping to implement it into the Genomics England NHS bioinformatics pipeline so that it is accessible nationally. It is also available as a separate package for anyone to use from anywhere in the world,” said study author Serena Nik-Zainal. 

Image Credit: Canva

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Breast Cancer / Cancer / Lung Cancer / Oncology / Sequencing