Volume 10 Supplement 1
Somatic mutations in cancer development
© Luzzatto; licensee BioMed Central Ltd. 2011
Published: 5 April 2011
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.
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.
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. 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].
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.
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