Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful
Synthesising the first generation of cancer genome sequencing, Vogelstein and colleagues concluded that about 140 genes can drive cancer when mutated, that a typical solid tumour has 2 to 8 driver mutations among tens of passengers, and that all drivers act through a dozen signalling pathways.
By 2013 hundreds of tumours had been exome- or genome-sequenced. This review organised the results. Common adult solid tumours carry an average of 33 to 66 non-synonymous somatic mutations, most of them passengers; paediatric tumours and leukaemias carry far fewer, and tumours caused by mutagens (lung, melanoma) or with mismatch-repair defects carry many more.
The authors listed about 138 driver genes (71 tumour suppressors, 54 oncogenes), described the mutational landscape as a few mountains (frequently mutated genes) and many hills, and grouped all drivers into 12 pathways governing cell fate, cell survival and genome maintenance. They emphasised that intratumoural heterogeneity, the relative paucity of new driver genes and the small number of drugs against tumour suppressor pathways set limits on precision oncology, and argued that early detection and prevention would be at least as important as new drugs.
The framework shaped how targeted-therapy panels, driver calling and basket trials were designed.
- About 140 driver genes identified; a typical common solid tumour has 2-8 driver mutations
- Average 33-66 non-synonymous mutations per common adult solid tumour, with mutagen-exposed tumours carrying 200 or more
- Drivers converge on 12 pathways in three core processes: cell fate, cell survival, genome maintenance
- Most drivers are tumour suppressors, which cannot be directly targeted by conventional drugs
- Argued that early detection would deliver more than new drugs for most cancers, foreshadowing the authors' later ctDNA work
There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.
- Counts of driver genes depend on statistical thresholds and have since grown with larger cohorts (about 300 in TCGA 2018)
- Focus on point mutations and small indels; structural variants, epigenetic drivers and non-coding drivers were under-counted
- Based on primary tumours; metastatic and treated tumours have additional drivers
- Pathway assignments are a simplification of overlapping networks