by ecancer Clare Sansom

All cancers are caused by one or more somatic mutations, but our understanding of the molecular mechanisms that generate these is still very limited.

We do know that some mutations are linked to exposure to particular carcinogens, such as ultraviolet light and tobacco smoke, and others to defects in DNA repair mechanisms.

Each process underlying somatic mutation generates a different characteristic pattern of mutations that has been termed a ‘signature’.

Until recently, our understanding of these mutational signatures has been based on studies of single genes known to be frequently mutated in cancer, and these have necessarily been limited.

However, sequencing technology is now advanced enough to allow the precise and fairly rapid sequencing of entire human genomes, including tumour genomes.

Following a pilot study on breast cancer, a large, international group of researchers led by Sir Michael Stratton of the Wellcome Trust Sanger Institute, Hinxton, UK has now analysed the genome sequences of 7,042 cancers, compared them with matched normal DNA and determined their mutational signatures.

This study was described as “a milestone” by BBC science journalist James Gallagher and as “fascinating and important” by Cancer Research UK.

The genomes studied covered thirty common or relatively common cancer types; the whole genome was sequenced in 507 cases and the protein-coding part of the genome (the exome) was sequenced in the remaining 6,535.

A total of 4,938,362 single base substitutions and small insertions / deletions (indels) were identified in the 7,042 genomes.

The number of mutations observed in each sample varied greatly; in general, paediatric tumours carried the fewest mutations and tumours associated with chronic exposure to carcinogens, such as lung tumours in smokers, the most.

The researchers analysed the base substitutions, indels, and chromosomal rearrangements present in each tumour sample and the sequence context of each mutation in order to distinguish groups of mutations that frequently occurred together.

Twenty-one of these so-called ‘mutational signatures’ could be distinguished in the complete set of cancer genomes; most individual cancer genomes contained more than one signature, with many different groups of signatures seen to occur together.

At least two signatures were observed in most cancer types, with the largest number – six – associated with cancers of the liver, uterus and stomach.

Similarly, seventeen of the 21 signatures were found in more than one cancer type.

Some of the signatures were characterized by one specific type of base substitution, while substitution types were represented almost equally in some others.

The signature that was observed in the most cancer samples – Signature 1, which was further subdivided into 1A and 1B – was the only one that had a strong correlation with the age of the patient at diagnosis; this suggests that these mutations will be acquired gradually throughout the patient’s lifetime.

Signature 2, a common signature that was found in 16 of the 30 cancer types, was characterized by mutation of cytosine to thymine or guanine, and the researchers proposed that this signature might arise from over-activity of a family of enzymes known as APOBEC cytidine deaminases.

Signature 13, which was found only in breast and cervical tumours, was also associated with over-activation of this enzyme family.

Other mutational signatures could be associated with DNA damage attributed to specific carcinogens.

For example, signature 4, which is common in lung cancer, has mutational features that are characteristic of the DNA damage associated with tobacco carcinogens; signature 7, found in melanoma and in head and neck cancer, includes mutation types that are known to be induced by ultra-violet radiation; and signature 11 can be associated with pre-treatment with temozolomide and other alkylating agents.

The researchers were, however, unable to decipher a probable origin for many of the other signatures.

Many tumours were found to contain clusters of hyper-mutation in small genomic regions, known as ‘kataegis’, in addition to one or more of the signatures.

Taken together, these results reveal something of the diversity of the molecular processes that underlie cancer development, including many distinct processes that have yet to be elucidated in detail; understanding these is likely to prove very useful in the development of novel therapies.

Reference

Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C. and over 70 others (2013). Signatures of mutational processes in human cancer. Nature, published online ahead of print 14 August 2013. doi:10.1038/nature12477