ABSTRACT
Genetic alterations of somatic cells can drive nonmalignant clone formation and promote cancer initiation. However, the link between these processes remains unclear hampering our understanding of tissue homeostasis and cancer development. Here we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and noncancer somatic evolution in 122 cancer types and 12 noncancer tissues. Mapping the alterations of these genes in 7953 pancancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and noncancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and noncancer somatic drivers, their literature support and properties are accessible at http://www.network-cancer-genes.org/.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
lisa.dressler{at}crick.ac.uk, michele.bortolomeazzi{at}crick.ac.uk, reda.keddar{at}crick.ac.uk, hrvoje.misetic{at}crick.ac.uk, giulia.sartini{at}crick.ac.uk, Amelia.Acha{at}crick.ac.uk, lucia.montorsi{at}crick.ac.uk, neshika{at}hotmail.co.uk, dimitra.repana{at}crick.ac.uk, joel.nulsen{at}crick.ac.uk, Jacki.Goldman{at}crick.ac.uk, marc.pollitt{at}crick.ac.uk, patrick.davis{at}crick.ac.uk, amy.strange{at}crick.ac.uk, karen.ambrose{at}crick.ac.uk, francesca.ciccarelli{at}crick.ac.uk
Added a panel to figure 1 to show the evidence supporting driver genes with alterations in non-coding sequences. This evidence is now explained in both the results, methods, and discussion. Modified figure 3 to show the number of altered canonical drivers in TCGA samples. Expanded the results to show the percentages of TCGA samples with more than one damaged cancer driver. Expanded the discussion to include new comments on the number of available healthy mutational screens.