Cancer: Directions for the drivers.


How important for cancer incidence and progression is genetic variation that affects gene expression? This fundamental question has received remarkably little attention in recent studies of cancer genomes, perhaps because of a prevailing view that the cancer-causing mutations that can be targeted by drugs are those that disrupt protein structure. In a paper published on Nature’s website today, Ongen et al. demonstrate how simultaneous gene-expression profiling and whole-genome genotyping can be used to dissect the regulation of gene transcription in colorectal cancer. The findings provide two thought-provoking insights: that cancerdriving changes may be identifiable among an excess of regulatory mutations, and that ‘cryptic’ regulatory genetic variation has the potential to modify cancer progression. It is well established that gene expression is altered in cancer. Despite their independent derivation, tumours of the same type tend to converge on a common, new gene-expression profile. Various studies, primarily from The Cancer Genome Atlas project, have noted differential transcription of tumour-driving and tumour-suppressing genes in advanced tumours, but so many gene transcripts are altered in these tumours that it is difficult to know which ones ‘drive’ the altered behaviour and which ones are ‘passengers’, just going along for the ride. Furthermore, epigenetic alterations — those that modify gene expression without involving sequence mutations — have been implicated in cancer, including colorectal cancer. Broad surveys of transcriptional and epigenetic changes in tumours have been conducted, but not on the scale and resolution achieved by Ongen and colleagues. They used a method known as RNA-Seq, in which the transcriptome of a cell (its whole complement of RNA molecules) is sequenced. Over the past couple of years, sequencing of the exome of cancer cells (in essence, just the protein-coding regions) has suggested that around 250 genes are mutated in cancer cells significantly more often than expected by chance. Many of these are pan-cancer genes, and some are tumour-type specific. It is less straightforward to perform similar analyses for regulatory DNA, for two reasons: we are just beginning to learn how to identify regulatory functions in the hundreds of kilobases that surround genes, and altered gene expression is often due to changes in genes located elsewhere in the genome. Ongen et al. overcome these limitations by focusing on changes in the ratio of expression of heterozygous alleles (sites at which the DNA sequence differs between the two copies of the sequence in a cell) between tumour and matched normal cells, as had also been done in another recent analysis of colorectal cancer. They call the hundreds of instances of this phenomenon that they find per sample ‘genes with allelic dysregulation’ (GADs). Although allele-specific expression can also be attributed to changes at other genes, it is highly likely that in many cases it is due to a locally acting regulatory mutation. Ongen et al. observe a significant correlation between the somatic (non-germline) mutation rate and altered allele-specific expression and, in each of the 103 matched normal–tumour pairs they analysed, approximately 200 transcripts showed a cancer-specific deviation in the allelic expression ratio at heterozygous sites. Their interpretation is that one allele is transcribed more than the other owing to the action of regulatory-sequence variation. The authors show that some of this deviation can be attributed to familiar cancerassociated mutation types, including loss of heterozygosity and copy-number alteration, and that some is due to inferred (yet to be defined) regulatory mutations. Tallying these instances over all of the samples, and taking two approaches to controlling for statistical biases, they arrive at a list of 71 GADs that occur more frequently in tumours than in normal cells, 9 of which are shared with an existing list of pan-cancer driver mutations. These observations provide a smoking gun for the idea that regulatory mutations can drive cancer. Perhaps there is no need to distinguish them with their own name, but the term ‘GPS mutations’ comes to mind, because they are instructing driver mutations on what to do, but it is not altogether clear that the cancer cells would not still attain a tumorous state without their help — much like a satellite-based navigation system instructing a driver on how to get somewhere. A related term, ‘back-seat driver’, has been invoked to describe another class of mutation that probably has a role in mediating cancer progression or metastatic spread, and that is conditional on the status of other driver mutations. Ongen and colleagues’ second major contribution is to suggest that, in addition to GPS mutations in GADs, another important C A N C E R

DOI: 10.1038/nature13649

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@article{Gibson2014CancerDF, title={Cancer: Directions for the drivers.}, author={Greg Gibson}, journal={Nature}, year={2014}, volume={512 7512}, pages={31-2} }