- Open Access
The (r)evolution of cancer genetics
© Ciccarelli; licensee BioMed Central Ltd. 2010
- Received: 10 May 2010
- Accepted: 03 June 2010
- Published: 11 June 2010
The identification of an increasing number of cancer genes is opening up unexpected scenarios in cancer genetics. When analyzed for their systemic properties, these genes show a general fragility towards perturbation. A recent paper published in BMC Biology shows how the founder domains of known cancer genes emerged at two macroevolutionary transitions - the advent of the first cell and the transition to metazoan multicellularity.
See research article http://www.biomedcentral.com/1741-7007/8/66
- Cancer Gene
- Cancer Genetic
- Cancer Protein
- Cancer Genome Project
- Affect Cell Differentiation
Recent advances in sequencing technologies and the launching of massive resequencing projects such as the Cancer Genome Project  have boosted the production of cancer genomics data. In the past few years, the entire repertoire of human exons has been sequenced in glioblastoma , pancreatic , breast and colorectal  cancers, and somatic mutations in selected genes have been mapped in multiple samples of renal  and lung  adenocarcinomas. In addition, the whole genomes of individuals affected by leukemia [7, 8], melanoma , glioma , breast [11, 12], and lung  cancers have been fully resequenced. All these studies have led to the identification of more than 1,000 potential cancer genes, and the list is likely to grow in the near future.
Cancer is a disease of multicellular organisms, where each cell is integrated within the larger system of the whole organism. In a recent paper in BMC Biology, Domazet-Lošo and Tautz  trace the evolutionary origins of known cancer genes and find that in most cases the origins coincide with one of two pivotal events in evolution - the emergence of the first cell or the transition towards metazoan multicellularity.
The newest piece of evidence that confirms how useful the global analysis of cancer genes can be is reported by Domazet-Lošo and Tautz , who analyze the origin of founder domains of known cancer proteins. Using a methodology called 'genomic phylostratigraphy', the authors are able to trace when the most conserved portions of known cancer proteins, which often correspond to functional domains, appeared in evolution. They observe two peaks, one at the origin of the ancestral cell and the other at the origin of metazoans.
Interestingly, these two peaks are enriched in two distinct groups of genes, namely 'caretakers' and 'gatekeepers', that contribute to cancer through different mechanisms. Caretakers are associated with the origin of the first cell and are involved in the control of genome stability and their modification increases the mutation rate and favors genomic instability. Gatekeepers originated with metazoans and their modifications directly or indirectly affect cell differentiation, growth and death. The different evolutionary origins of these genes suggest two distinct mechanisms of carcinogenesis. The first deals with the basic functions of the cell, such as the control of genome stability, that, very reasonably, were established already in the ancestral eukaryotic cell. The second mechanism is intimately connected to multicellularity and to the interactions between cells within a complex organism. This observation puts cancer in the context of macroevolutionary transitions and links tumorigenesis to the disruption of processes that are essential for survival of the cell and for its communication with the external environment.
The emerging heterogeneity of the cancer genomic landscape has been used to question the usefulness of large-scale screenings, the main concern being that the discovery of rare mutations adds very little to the overall knowledge of cancer genetics. Approaches that focus on the identification of global features, more than to the study of single genes, show instead that a comprehensive catalogue of cancer genetic determinants is instrumental to trace recurrent patterns in their systems-level and evolutionary properties.
The author thanks Matteo D'Antonio and Adnan Syed for help with the figure. The author is supported by the Start-Up grant of the Italian Association for Cancer Research (AIRC).
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