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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.
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.
Cancers are defined as much by the tissue they come from as by the mutations they carry, which is why the same drug can work in one organ and fail in another with the same mutation. TCGA is the shared public dataset behind most modern biomarkers and target discovery.
Every screening programme rests on this paper: if cancer arrives through a polyp that takes years to progress, then finding and removing polyps prevents cancer rather than merely catching it early.
Shares Ludmil B. Alexandrov, Driver and passenger mutations: the refined somatic mutation theory, Science, Mutational signature.
Shares Science, Theories of cancer: how the ideas connect, Mutational signature, Tumour mutational burden (TMB).
Shares Kenneth W. Kinzler, Bert Vogelstein, Science, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Mutational signature, Tumour mutational burden (TMB), Tumour heterogeneity and clonal evolution, Whole-exome & whole-genome sequencing.
Shares Genetic alterations during colorectal-tumor development, Bert Vogelstein, Somatic mutation theory of cancer, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Science, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Whole-exome & whole-genome sequencing.
Shares Driver and passenger mutations: the refined somatic mutation theory, Oncogene addiction, Theories of cancer: how the ideas connect, Somatic mutation theory of cancer.