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Signatures of Mutational Processes in Cancer

Association between aetiology of most common cancers and validated mutational signatures
19 Aug 2013
Translational Research

All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. A group of international researchers led by scientists from the Cancer Genome Project, Wellcome Trust Sanger Institute, one of the world's leading genome centres, analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. They published their findings on 14 August 2013, in advanced online publication of prestigiousNaturejournal.

Some of mutational signatures 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 from this study reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

The first comprehensive catalogue of mutational processes that drive tumour development

In their article, the researchers have provided the first comprehensive compendium of mutational processes that drive tumour development. Together, these mutational processes explain most mutations found in 30 of the most common cancer types.  Each mutational process leaves a particular pattern of mutations, a signature, in the genomes of cancers it has caused. By studying genomes of people with the most common forms of cancer, the team uncovered signatures of processes that mutate DNA. For many of the signatures, they also identified the underlying biological process responsible.

According to Ludmil Alexandrov, the first author of the study from the Wellcome Trust Sanger Institute, the researchers are now beginning to understand the complicated biological processes that occur over time and leave residual mutational signatures on cancer genomes.

All of the cancers contained two or more signatures, reflecting the variety of processes that work together during the development of cancer. However, different cancers have different numbers of mutational processes. For example, two mutational processes underlie the development of ovarian cancer, while six mutational processes underlie the development of liver cancer. Some of the mutational signatures are found in multiple cancer types, while others are confined to a single cancer type. Out of the 30 cancer types, 25 had signatures arising from age-related mutational processes. Another signature, caused by defects in repairing DNA due to mutations in BRCA1 and 2 genes, was found in breast, ovarian and pancreatic cancers.

According to Dr Serena Nik-Zainal, the second author of the paper from the Wellcome Trust Sanger Institute, this map of the events that cause the majority of cancers in humans is an important step to discovering the processes that drive cancer formation.

The team found that a family of enzymes, which is known to mutate DNA, was linked to more than half of the cancer types. These enzymes, known as APOBECs, can be activated in response to viral infections. It may be that the resulting signatures are collateral damage on the human genome caused by the enzymes' actions to protect cells from viruses.

Recently, the research team described a remarkable pattern of mutation in breast cancer whereby small regions of the genome are deluged with mutations. They now show that this process, known as kataegis, is present in most cancers. Researchers speculate that the onset of kataegis may also be linked to the activation of APOBEC enzymes.

"We have uncovered the archaeological traces within cancer genomes of the diverse mutational processes that lead to the development of most cancers," says Professor Sir Mike Stratton, lead author of the paper and Director of the Wellcome Trust Sanger Institute. This compendium of mutational signatures and the insights into the mutational processes underlying them will have profound implications for the understanding of cancer development with potential applications in disease prevention and treatment.

The authors declare no competing financial interests. They thanked the Wellcome Trust for support (grant reference 098051) together with many other funding bodies and individuals.

Click on the hiperlinks to download the computational framework for deciphering mutational signatures and all mutational catalogues, and the complete set of somatic mutations


Alexandrov LB, Nik-Zainal S, Wedge DCet al. Signatures of mutational processes in human cancer. Nature 2013 Aug 14. doi: 10.1038/nature12477. [Epub ahead of print].

Last update: 19 Aug 2013

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