Large whole-genome analysis of cancer genome reveals new, rare mutational signatures

A large-scale, whole-genome analysis of more than 12,000 cancers reveals previously unreported mutational signatures, including tumor-specific rare signatures, according to new research. Not only do the findings introduce the concept of common versus rare mutational signatures within each cancer type, but they also highlight how such insights could be used to enhance personalized cancer treatments and diagnoses. A cancer genome is often a distorted amalgamation of thousands of genetic mutations. Modern whole-genome sequencing (WGS) approaches allow for comprehensive cancer genome analyses, revealing characteristic combinations of mutations that have contributed to a particular cancer. These patterns, also called mutational signatures, can describe the mutational processes that led to tumor development. To date, many mutational signatures in cancer have been reported. Significantly adding to this knowledge base, Andrea Degasperi and colleagues performed mutational signature analysis on 12,222 WGS cancers from patients recruited from UK National Health Service Genomic Medicine Centers across England as part of the Genomics England 100,000 Genomes Project. Comparing their results with those from two smaller, open-access cancer WGS datasets, the International Cancer Genome Consortium and the Hartwig Medical Foundation, Degasperi et al.’s analysis involved more than 18,000 WGS cancers in total. While the findings confirmed many previously reported mutational signatures, the analysis identified previously unknown and rarer varieties, adding 40 single-base and 18 double-base substitution signatures to the current mutational signature collection. The authors show that for each tumor type, cancers can have a limited number of common mutational signatures and several rarer signatures, which occur at low frequency in the population. The dataset also provided clues about the underlying causes of a cancer, such as environmental exposure from smoking or UV light, for example, or internal, cellular malfunctions.