Abstract
BackgroundGenetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development.ResultsHere, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer 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 non-cancer 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.ConclusionsOur 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 non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/.
Highlights
Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation
Genetic alterations conferring selective advantages to cancer cells are the main drivers of cancer evolution and hunting for them has been at the core of international cancer genomic efforts [1,2,3]
The identification of drivers as genes under positive selection or with a higher than expected mutation frequency within a cohort of patients has biased the current cancer driver repertoire towards genes whose coding point mutations or small indels frequently recur across patients. This strongly impairs the ability to map the full extent of driver heterogeneity leading to an underappreciation of the driver contribution of rarely altered genes and those modified through non-coding or gene copy number alterations, Fig. 5 Network of Cancer Genes and Healthy Drivers (NCGHD) annotations of driver genes. a Example of the type of annotation provided in NCGHD for cancer and healthy drivers
Summary
Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. Given the instability of the cancer genome, distinguishing driver alterations from the rest relies on analytical approaches that identify genes altered more frequently than expected or quantify the positive selection acting on them [4,5,6] The results of these analyses have greatly expanded our understanding of the mechanisms driving cancer evolution, revealing high heterogeneity across and within cancers [7,8,9]. Deep sequencing screens of non-cancer tissues have started to map positively selected genetic mutations in somatic cells that drive in situ formation of phenotypically normal clones [10, 11] Many of these mutations hit cancer drivers, sometimes at a frequency higher than the corresponding cancer [12,13,14,15,16]. Addressing these questions will clarify the genetic relationship between tissue homeostasis and cancer initiation, with profound implications for cancer early detection
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