Analysis of Somatic Point Mutations in Exome Sequences

Large-scale analysis of over 20 tumour types increases catalogue of cancer genes

A landmark study across many cancer types reveals that the universe of cancer mutations is much bigger than previously thought. By analysing the genomes of thousands of patients' tumours, a Broad Institute-led research team has discovered many new cancer genes — expanding the list of known genes tied to these cancers by 25%.

Moreover, the study shows that many key cancer genes still remain undiscovered. The team's work, which lays a critical foundation for future cancer drug development, also shows that creating a comprehensive catalogue of cancer genes for scores of cancer types is feasible with as few as 100,000 patient samples.

Over the past 30 years, scientists have found evidence of about 135 genes that play causal roles in one or more of the 21 tumour types analysed in the study. The new report not only confirms these genes, but increases the catalogue of cancer genes by one-quarter. It uncovers new genes with biological roles in various cell processes. The researchers' results appear in print in the scientific journal Nature.

The study results

Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, the group analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types.

They found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Their analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis.

Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. They estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency.  The researchers estimate that they will need to analyse, on average, about 2,000 samples of each cancer type in order to catalogue the vast majority of these mutations – or about 100,000 samples across roughly 50 tumour types.

The tumour types analysed included those in which lots of mutations occur – such as melanoma and forms of lung cancer, and those that have a much lower frequency of mutations – such as rhabdoid and medulloblastoma, both childhood cancers.

The altered genes that the team pinpointed will need to be followed up to determine which, if any, could be important targets for drug development. In the meantime, the new work offers a wider view of the cancer genomics universe, and tantalising clues about what remains to be discovered if more samples are analysed.

This work was conducted as part of the Cancer Genome Atlas, a project of the USA National Cancer Institute and the National Human Genome Research Institute.


Lawrence M, Stojanov P, Mermel CH,et al. Discovery and saturation analysis of cancer genes across 21 tumor types. Nature 2014; 505: 495-501. doi: 10.1038/nature12912.