Signatures of mutational processes in human cancer

Abstract

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Figure 1. The prevalence of somatic mutations across human cancer types

Every dot represents a sample while the red horizontal lines are the median numbers of mutations in the respective cancer types. The vertical axis (log scaled) shows the number of mutations per megabase while the different cancer types are ordered on the horizontal axis based on their median numbers of somatic mutations. We would like to thank Gad Getz and colleagues for the design of this figure.

Figure 2. Validated mutational signatures found in human cancer

Each signature is displayed according to the 96 substitution classification defined by the substitution class and sequence context immediately 3′ and 5′ to the mutated base. The probability bars for the six types of substitutions are displayed in different colors. The mutation types are on the horizontal axes, while vertical axes depict the percentage of mutations attributed to a specific mutation type. All mutational signatures are displayed based on the trinucleotide frequency of the human genome. A higher resolution of each panel is found respectively in Supplementary Figures 2 to 23.

Figure 3. The presence of mutational signatures across human cancer types

Cancer types are ordered alphabetically as columns while mutational signatures are displayed as rows. “Other” indicates mutational signatures for which we were not able to perform validation or for which validation failed (Supplementary Figs 24 to 28). Prevalence in cancer samples indicates the percentage of samples from our dataset of 7,042 cancers in which the signature contributed significant number of somatic mutations. For most signatures, significant number of mutations in a sample is defined as more than 100 substitutions or more than 25% of all mutations in that sample.

Figure 4. The contributions of mutational signatures to individual cancers of selected cancer types

Each bar represents a typical selected sample from the respective cancer type and the vertical axis denotes the number of mutations per megabase. Contributions across all cancer samples could be found in Supplementary Figures 29 to 58. Summary of the total contributions for all operative mutational processes in a cancer type could be found in Supplementary Figures 59 to 88. “Other” indicates mutational signatures for which we were not able to perform validation or for which validation failed (Supplementary Figs 24 to 28).

Figure 5. Mutational signatures with strong transcriptional strand bias

Mutations are shown according to the 192 mutation classification incorporating the substitution type, the sequence context immediately 5′ and 3′ to the mutated base and whether the mutated pyrimidine is on the transcribed or untranscribed strand. The mutation types are displayed on the horizontal axis, while the vertical axis depicts the percentage of mutations attributed to a specific mutation type. A higher resolution version of each panel is found respectively in Supplementary Figures 89 to 95.

Figure 6. Kataegis in three cancers

Each of these “rainfall” plots represents an individual cancer sample in which each dot represents a single somatic mutation ordered on the horizontal axis according to its position in the human genome. The vertical axis denotes the genomic distance of each mutation from the previous mutation. Clusters of mutations in kataegis are arrowed.