Substitution mutational signatures in whole-genome–sequenced cancers in the UK population

Abstract

Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage, and repair processes that have arisen in each patient’s cancer. We performed mutational signature analyses on 12,222 whole-genome–sequenced tumor-normal matched pairs from patients recruited via the UK National Health Service (NHS). We contrasted our results with two independent cancer WGS datasets—from the International Cancer Genome Consortium (ICGC) and the Hartwig Medical Foundation (HMF)—involving 18,640 whole-genome–sequenced cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. We show for each organ that cancers have a limited number of common signatures and a long tail of rare signatures, and we provide a practical solution for applying this concept of common versus rare signatures to future analyses.

Strand-resolved mutagenicity of DNA damage and repair

“…Cancer genomes are the result of diverse mutational processes 1,13 , often accumulated over decades, making it challenging to identify and subsequently interpret their relative roles in generating spatial and temporal mutational asymmetries. The relative contribution of DNA damage, surveillance, and repair processes to observed patterns of mutational asymmetry remains poorly understood, though mapping of DNA damage [14][15][16][17] and repair intermediates 18,19 have provided key insights.…”

Estimating the number of diseases – the concept of rare, ultra-rare, and hyper-rare

“…Fortunately, as we increase our ability to distinguish and understand the disease by more precisely measuring variation, we will be better able to provide prognosis and treatment to individual patients. Numerous examples of this come from the profound increase in nucleic acid sequencing data available to distinguish related cancers leading to improved specific therapeutics to treat them ( Degasperi et al., 2022 ; Incerti et al., 2022 ). To this end, many fields are benefiting from our unprecedented ability to collect patient data and make sense of it in novel ways, as exemplified by surveillance of diseases by mobile device data collection ( Wood et al., 2019 ).…”

“…When the phenotype and treatment responses vary according to the specific type of mutation, this is normally considered a basis for subgrouping into different stages or even disease entities. As genome-wide analyses of tumors have increased profoundly over the last few years ( Degasperi et al., 2022 ), they have already led to an improved appreciation of distinct malignant diseases ( Calderaro et al., 2017 ). Additionally, liquid biopsy analysis has the potential to revolutionize our understanding of tumor evolution by providing information in real-time, though research into the biology of blood-borne tumor material is still in its infancy ( Hagey et al., 2021 ).…”

“…To this end, we believe that many more studies are needed before it is possible to reach any consensus on how many tumor subtypes exist and to what extent they represent different entities. However, there is no doubt that there are many forms of tumors, and that the characterization of subtypes will continue ( Degasperi et al., 2022 ; https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga ), likely resulting in numerous novel cancer subgroups being classified as different diseases.…”

“…Although the number of 10,000 is practical for many purposes ( Haendel et al., 2020 ), we believe that it is a gross underestimate when considering the number of potential diseases. There are two primary reasons: First, diseases depend on our ability to define and distinguish them, which will continually increase with our understanding and capacity to diagnose them ( Smedley et al, 2021 ; Chong et al., 2015 ; Degasperi et al., 2022 ; Ferreira 2019 ). Second, disease can be influenced or caused by a myriad of factors including infections, allergens, physical insults, toxins, environmental conditions, such as altitude or humidity, as well as both inherited and acquired genetic variants ( Figure 1 ).…”