Alan Ashworth

During the past few years, the advent of hugely powerful DNA-sequencing technologies has delivered unprecedented insight into the nature of cancer genomes3. Hundreds of examples of genomes from several cancer types have already been produced, and this process will continue so that a definitive overview of cancer genomics can eventually be achieved. Nevertheless, it seems apposite to take stock of the themes that are emerging from comparisons of the genomes of different tumour types2,4 — studies that are giving us a fascinating first peek at the common mutational events and processes that shape cancer genomes.

The first impression that emerges from these comparisons is of the tremendous variation. Some types of cancer have, on average, relatively few genetic changes, whereas others show extraordinary mutational complexity. It is likely that most mutations in cancer genomes represent collateral damage that is unrelated to pathogenesis, but studies seeking candidates for driver mutations — those that contribute to the disease state5 — are revealing that both the number and nature of these candidates also differ considerably between cancers3. In some cases, we are seeing distinct cancer types with alterations in the same cellular pathway brought about through driver mutations in different genes.

Mutual exclusivity of mutations in genes or pathways is also becoming apparent2,3, providing clues as to which genes or pathways have non-redundant roles in oncogenesis. Using such data, we may eventually be able to understand the totality of biological perturbations that, acting together, result in the phenotypic diversity of human cancer. There is also the potential to deconvolve the order in which pathways are altered during disease progression, which is likely to be non-random owing to genetic interactions6. Gaining understanding of these two issues may be key to successful prevention and treatment strategies.

Comparing the type and frequency of genetic alterations, and the overall genomic structure, in different tumour classes also gives insight into the underlying mutational processes at play4. The accumulation of mutagenic cellular processes, endogenous and environmental exposures, and DNA-repair defects over many years or decades results in genomic 'scars'7 that can help us to understand the cause of the disease in an individual. The mutagenic fingerprints of tobacco smoking and sunlight exposure, for example, are obviously manifest in some cancers, but new phenomena are also being described and neologisms coined to describe them, such as chromothripsis for the shattering of individual chromosomes8 or kataegis for discrete genomic regions peppered with mutations9. Many other previously unknown mutational processes also seem to be involved in the development of particular cancers. Studying these may reveal other influences on cancer development4.

An enormous amount has already been gleaned from these initial analyses, but much remains to be done. First, there is a strong case for completing a comprehensive and detailed survey of the entire panoply of human cancers. Paradoxically, rather than increasing complexity, this should allow further common themes to emerge from the noise. Second, most analyses of driver mutations have focused on protein-coding regions, which comprise only about 1% of the human genome. But it seems probable that studying non-coding regions will reveal a wealth of cancer-related mutations. Third, epigenetic alterations to the genome — which affect gene expression without changing the underlying DNA sequence — that cause or occur during cancer development need to be integrated into this landscape. Fourth, most of the tumours studied so far have been primary cancers before treatment; metastatic and treatment-resistant genomes also need to be studied in detail. Last, several studies have highlighted the genetic variation between individual cells within a tumour, and further analysis is needed to ascertain the prevalence of this phenomenon.