- 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://0-www.biomedcentral.com.brum.beds.ac.uk/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).
- The International Cancer Genome Project. [http://www.icgc.org]
- Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 2008, 321: 1807-1812. 10.1126/science.1164382.PubMed CentralView ArticlePubMedGoogle Scholar
- Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, et al: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008, 321: 1801-1806. 10.1126/science.1164368.PubMed CentralView ArticlePubMedGoogle Scholar
- Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, et al: The genomic landscapes of human breast and colorectal cancers. Science. 2007, 318: 1108-1113. 10.1126/science.1145720.View ArticlePubMedGoogle Scholar
- Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, et al: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010, 463: 360-363. 10.1038/nature08672.PubMed CentralView ArticlePubMedGoogle Scholar
- Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008, 455: 1069-1075. 10.1038/nature07423.PubMed CentralView ArticlePubMedGoogle Scholar
- Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, et al: DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008, 456: 66-72. 10.1038/nature07485.PubMed CentralView ArticlePubMedGoogle Scholar
- Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, et al: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009, 361: 1058-1066. 10.1056/NEJMoa0903840.PubMed CentralView ArticlePubMedGoogle Scholar
- Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordóñez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, et al: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010, 463: 191-196. 10.1038/nature08658.PubMed CentralView ArticlePubMedGoogle Scholar
- Clark MJ, Homer N, O'Connor BD, Chen Z, Eskin A, Lee H, Merriman B, Nelson SF: U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line. PLoS Genet. 2010, 6: e1000832-10.1371/journal.pgen.1000832.PubMed CentralView ArticlePubMedGoogle Scholar
- Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S: Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009, 461: 809-813. 10.1038/nature08489.View ArticlePubMedGoogle Scholar
- Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Lin L, et al: Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 2010, 464: 999-1005. 10.1038/nature08989.PubMed CentralView ArticlePubMedGoogle Scholar
- Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordoñez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, et al: A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010, 463: 184-190. 10.1038/nature08629.PubMed CentralView ArticlePubMedGoogle Scholar
- Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med. 2004, 10: 789-799. 10.1038/nm1087.View ArticlePubMedGoogle Scholar
- Domazet-Loso T, Tautz D: Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa. BMC Biol. 2010, 8: 66-10.1186/1741-7007-8-66.PubMed CentralView ArticlePubMedGoogle Scholar
- Lin J, Gan CM, Zhang X, Jones S, Sjöblom T, Wood LD, Parsons DW, Papadopoulos N, Kinzler KW, Vogelstein B, Parmigiani G, Velculescu VE: A multidimensional analysis of genes mutated in breast and colorectal cancers. Genome Res. 2007, 17: 1304-1318. 10.1101/gr.6431107.PubMed CentralView ArticlePubMedGoogle Scholar
- Jonsson PF, Bates PA: Global topological features of cancer proteins in the human interactome. Bioinformatics. 2006, 22: 2291-2297. 10.1093/bioinformatics/btl390.PubMed CentralView ArticlePubMedGoogle Scholar
- Rambaldi D, Giorgi FM, Capuani F, Ciliberto A, Ciccarelli FD: Low duplicability and network fragility of cancer genes. Trends Genet. 2008, 24: 427-430. 10.1016/j.tig.2008.06.003.View ArticlePubMedGoogle Scholar
- Syed AS, D'Antonio M, Ciccarelli FD: Network of Cancer Genes: a web resource to analyze duplicability, orthology and network properties of cancer genes. Nucleic Acids Res. 2010, 38: D670-D675. 10.1093/nar/gkp957.PubMed CentralView ArticlePubMedGoogle Scholar
- Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR: A census of human cancer genes. Nat Rev Cancer. 2004, 4: 177-183. 10.1038/nrc1299.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to 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.