Somatic mutations in cancer development
- Lucio Luzzatto1Email author
https://doi.org/10.1186/1476-069X-10-S1-S12
© Luzzatto; licensee BioMed Central Ltd. 2011
Published: 5 April 2011
The Erratum to this article has been published in Environmental Health 2011 10:S16
Abstract
The transformation of a normal cell into a cancer cell takes place through a sequence of a small number of discrete genetic events, somatic mutations: thus, cancer can be regarded properly as a genetic disease of somatic cells. The analogy between evolution of organisms and evolution of cell populations is compelling: in both cases what drives change is mutation, but it is Darwinian selection that enables clones that have a growth advantage to expand, thus providing a larger target size for the next mutation to hit. The search for molecular lesions in tumors has taken on a new dimension thanks to two powerful technologies: the micro-arrays for quantitative analysis of global gene expresssion (the transcriptome); and ‘deep’ sequencing for the global analysis of the entire genome (or at least the exome). The former offers the most complete phenotypic characterization of a tumor we could ever hope for – we could call this the ultimate phenotype; the latter can identify all the somatic mutations in an individual tumor – we could call this the somatic genotype. However, there is definitely the risk that while we are ‘drowned by data, we remain thirsty for knowledge’. If we want to heed the teachings of Lorenzo Tomatis, I think the message is clear: we ought to take advantage of the new powerful technologies – not by becoming their slaves, but remaining their masters. Identifying somatic mutations in a tumor is important not because it qualifies for ‘oncogenomics’, but because through a deeper understanding of the nature of that particular tumor it can help us to optimize therapy or to design new therapeutic approaches.
Keywords
Introduction
Headings of one of the first and on of the last publications by Lorenzo Tomatis.
Pedigree of a family with a high rate of breast cancer and ovarian cancer: the increased tendency to developing cancer shows a Mendelian autosomal dominant pattern of inheritance, suggesting that a single gene is largely responsible.
In this extended family there were 3 cases of hairy cell leukaemia (HCL): their co-existence can be hardly a coincidence, since HCL is one of the rarest forms of B cell leukaemia. Here the pattern is not Mendelian, suggesting that several genes and/or environmental factors are involved.
Three patients with hairy cell leukaemia in the same family.
Meta-analysis of the quantitative effect of a polymorphic allele of the TGF b receptor gene on the frequency of some types of tumors.
A genetic polymorphism in the coding sequence of the TGF-β receptor gene influences the risk of cancer.
With respect to the environment, I think the most lasting monumental memorial to Lorenzo is the series of IARC publications on carcinogenic agents which, in the jargon of the cognoscentes, are known simply as The Monographs. Rarely has an international agency been able to generate publications (each one the product of a collegial effort) with so much scientific content; even more rarely has this taken place consistently in dozens of volumes over some thirty years, to the extent that the Monographs are universally regarded as the ultimate authority on their individual topics; and probably never has a single person – namely Tomatis himself – through his scientific rigor, his incredible dedication, and his unique ability to catalyze consensus whenever possible, contributed so much to a successful venture of this nature.
A cartoon illustrating current views of the origin of cancer, which is consequent on n successive somatic mutations. The final result is a clonal population of cells with highly disregulated growth. It can be presumed that in fact each one of the mutational steps entails a growth advantage, even if small: this increases the number of cells that can be targeted by the next mutation. The term n-1 is used to indicate the penultimate step in the pathway, because the number n is not fixed: it is estimated that it may range, for the majority of tumors, from 3 to 6 or even more.
Figure 8
Inherited mutations can increase cancer proneness through different mechanisms. The top section of the cartoon is a schematic of the process outlined in Fig. 5. The middle section illustrates how an increased rate of somatic mutations can produce an accelerated rate of the oncogenic pathway: this is the case for instance for patients with Fanconi anemia, who have a serious defect in DNA repair and often develop cancer at a young age. The bottom section illustrate that the number of steps for a normal cell to become a cancer cell is cut by one if the first mutation is an inherited (germ-line) mutation rather than an acquired somatic mutation: this is the case for instance for patients who have an APC mutation and present with familial adenomatous polyposis.
In order to understand the pathogenesis of tumors we must consider their very extensive variety: not only can they arise in virtually every possible cell type in the body, but even within the set of tumors arising from a specific type of cell there is marked heterogeneity, some of it well explored and some yet to be unravelled. The somatic mutation-Darwinian selection model of cancer is appropriately versatile: we can presume, and we know in specific cases that different genes are involved: some 400 have been already identified[18]. To this end, the methodology that has given the highest returns has been cytogenetic analysis, which has spotted (i) chromosomal translocations harbouring fusion genes or rearrangements that dysregulate gene expression, as well as (ii) loss of heterozigosity betraying deletions. In other cases somatic mutations have been discovered in genes already known to have germ-line mutations in cancer-prone families, or by deliberately testing for somatic mutations in candidate genes. Not surprisingly, many of the genes involved belong to sets that are relevant to broad functions within the cell (the buzz-term today is gene ontology): particularly the cell cycle, signalling, regulation of transcription, apoptosis and, once again, genome stability (DNA repair)[19, 20].
A graphic representation (current referred to as a cyclo-plot) of the multiple defects detected in the genome of a tumor (a small-cell lung cancer cell line) by deep sequencing. Individual chromosomes are depicted on the outer circle followed by concentric tracks for point mutation, copy number and rearrangement data relative to mapping position in the genome. Arrows indicate examples of the various types of somatic mutation present in this cancer genome. From Stratton et al., 2009 (ref. 29).
Figurative depiction of the landscape of somatic mutations present in a single cancer genome.
A cartoon illustrating the central role of chance in cancer formation, based on the fact that somatic mutations are stochastic events. Inherited factors (see text and Fig. 6) can modulate the process, but they somatic mutations are still needed for the onset of cancer; and environmental factors work in large measure by increasing either the mutation rate (mutagenic agents) or the number of cell divisions (e.g. with an inflammatory process, such as one caused for instance by Helicobacter pylori).
A new methodology makes it relatively easy to measure in any individual the intrinsic rate of somatic mutation. In two conditions known to be associated with cancer proneness the rate of somatic mutation is markedly increased over that observed in a control group.
Notes
Declarations
Acknowledgements
This article has been published as part of Environmental Health Volume 10 Supplement 1, 2011: Proceedings of the First Lorenzo Tomatis Conference on Environment and Cancer. The full contents of the supplement are available online at http://www.ehjournal.net/supplements/10/S1.
Authors’ Affiliations
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