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Ciccarelli BMC Biology 2010, 8:74 http://www.biomedcentral.

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The (r)evolution of cancer genetics
Francesca D Ciccarelli*
See research article http://www.biomedcentral.com/1741-7007/8/66

Abstract 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.

Increasing number and heterogeneity of cancer genes Recent advances in sequencing technologies and the launching of massive resequencing projects such as the Cancer Genome Project [1] have boosted the production of cancer genomics data. In the past few years, the entire repertoire of human exons has been sequenced in glio­ blastoma [2], pancreatic [3], breast and colorectal [4] cancers, and somatic mutations in selected genes have been mapped in multiple samples of renal [5] and lung [6] adenocarcinomas. In addition, the whole genomes of individuals affected by leukemia [7,8], melanoma [9], glioma [10], breast [11,12], and lung [13] 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. This massive amount of information will have a huge impact on our understanding of cancer genetics, even more so considering that the biological role of most mutations is still obscure. These first unbiased screenings have led to the identification of novel and unsuspected determinants of cancer, such as the isocitrate dehydro­ genase enzyme genes IDH1 and IDH2, which have been found mutated in glioblastoma multiforme [2]. They have also started to question some cornerstones of cancer
*Correspondence: francesca.ciccarelli@ifom-ieo-campus.it 1 Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy

biology, such as the description of cancer as a unique disease driven by the somatic modification of a few key regulators. The progressive identification of novel mutated genes is expanding the ‘cast of actors’ [14] whose mutations might be causally involved in driving cancer. Moreover, given the high heterogeneity of genes mutated in different cancer types (Figure  1), the overall ‘plot’ is becoming more intricate. The emerging picture suggests that there may be distinct genetic routes to reach the common aftermath of all tumorigenic processes, which is uncontrolled cell proliferation. For example, as many as 12 core pathways are disrupted in the majority of pancreatic cancers through multiple somatic mutations [3]. This opens up an intriguing scenario where the deregulation of key pathways for tumorigenesis repre­ sents only the final step of a more general perturbation of cellular activity. The cell is seen as an integrated system in which all processes form a tightly interconnected network more than as an ensemble of independent pathways. In this context, the effect of somatic mutations occurring in the cancer genome should be interpreted in the light of their broader impact on the system’s equilibrium. 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, Domazet­Lošo and Tautz [15] 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.

Systems-level perturbations of cancer-related mutations The first attempts to study cancer genes using more systematic approaches have already proved successful in broadening our knowledge of the genetic determinants of cancer. A multidimensional analysis has combined sequence similarity, functional annotations, protein­ protein interactions, and molecular pathways to examine genes mutated in breast and colorectal cancers [16]. This study showed that while processes involved with

© 2010 Ciccarelli; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

com/1741-7007/8/74 Page 2 of 4 Cancer Gene Census Colorectal Glioblastoma Lung Breast Pancreatic Kidney Melanoma Lung Breast Leukemia Exon sequencing Genome sequencing TP53 PIK3CA KRAS NF1 RB1 CDKN2A EGFR NRAS PTEN APC SMAD4 ERBB2 IDH1 KIAA0774 GNAS MLLT3 FLT3 NTRK3 BAI3 NF2 EP300 SORL1 ALK ELN NUMA1 SKP2 FLNC CDC6 ZNF521 CPAMD8 KDM5C DLEC1 KDM6A GPR112 PALB2 FRMPD4 STK11 RUNX1T1 FBXW7 SMARCA4 GLI1 NUP214 COL1A1 ZNF217 KDR ADAMTS20 PIK3R1 LAMA1 BRAF TCF1 F8 COL3A1 EPHA3 PDGFRA SEMA5B PTPRD UVRAG ADAM29 GUCY1A2 NOTCH1 SETD2 AKAP6 SF3B1 ETV5 LRRC7 BRCA1 TRIOBP TBX18 NPM1 CDK4 BCL11A TGFBR2 TLR9 MYH9 BCL9 ABCB11 PCSK5 KCNC2 MLL2 RET CIC ATM MYO18B DPP10 NTRK1 Figure 1. The latter can be genetically repressive (red) or dominant (orange). which is a literature-based collection of known cancer genes [20]. Of those. more than 1. either in large-scale screenings or in the cancer gene census. . 8:74 http://www.000 human genes have been identified that carry proven or potential driver mutations involved in cancer progression. So far. Heterogeneity of genes mutated in different cancer types. which broadly correspond to tumor-suppressors and caretakers and to oncogenes.biomedcentral.Ciccarelli BMC Biology 2010. respectively. This distinction cannot be done for genes identified through large-scale screenings that involve either massive exon [2-6] or whole-genome [7-13] resequencing. only 85 genes have been found mutated in at least two studies.

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