A very intriguing (and worrisome) paper published by Science (Tomasetti C. and Vogelstein B., Variation in cancer risk among tissues can be explained by the number of stem cell divisions, Science 2015, 347 no. 6217 pp. 78-81) casts doubt on the relevance of environmental factors in carcinogenesis.
In addition, it posits that a wide array of cancer types arise from an increased rate of random mutations occurring in tissues with high replication rates. The Authors conclude that, out of 31 cancer types considered, 22 were primarily associated with random genetic mutations (they called these “R-tumors” – the R standing for “random”), and nine were associated with environmental factors on top of these random mutations (deterministic tumors, or “D-tumors”). About 70% of these tumors were claimed to be predominantly determined by random mutations (“bad luck”) and not environmental factors.
Unfortunately, comments by the specialized and lay media have emphasized the “bad luck” aspect, drawing the very simplistic and misguided conclusion that cancer onset is no longer a matter linked to environmental and lifestyle.Instead, it (almost) would entirely rely on stochastic fluctuations, which was translated into “bad luck”.
I reckon that, if it not for its seriousness for cancer patients,we should be bemused by this episode in the long standing controversy about cancer theories. First of all, environmental pollution and lifestyle are relevant issues in disease pathogenesis at large (not only in carcinogenesis). They should not be overlooked or belittle. For the media to claim that lifestyle isn’t important, based on misinterpretations of what the research shows, is highly irresponsible. These arguments, especially when they are widely amplified by media articles, are likely to open the door to an abdication of responsibility when it comes to environmental health by industry and international, national and local public health institutions. Why spend funds on preventing environmental threats or in performing safety tests when pollution doesn’t matter? Statements such as those of Tomasetti and Vogelstein and their uninformed media followers only generate discouragement and confusion in our globalized world.
Secondly, the claim that ‘random mutations’ are associated with increased frequency of cancer, clearly supports the somatic mutation theory of cancer (SMT), according to which cancer arises as a consequence of point mutations affecting proto-oncogenes or anti-oncogenes. Yet, the report does not provide evidence backing up such claim. Indeed, if cancer rates are statistically associated with ‘random mutations’, the mechanistic link between those mutations and cellular biochemical pathways becomes unavoidably lost. High frequency of those genomic changes has been found in some cancers. However, this correlation only suggests that tissues with high replicating rate display higher chance to develop tumors. Notwithstanding, genetic alterations found in cancerous tissues are not cancer-specific, given that they are frequently observed in normal tissues (Washington C, Dalbegue F, Abreo F, et al. Loss of heterozygosity in fibrocystic change of the breast: genetic relationships between benign proliferative lesions and associated carcinomas. Am J Pathol 2000;157:323-9), and mostly in tissues affected by reactive or inflammatory processes (Yamanishi Y, Boyle DL, Rosengren S, et al. Regional analysis of p53 mutations in rheumatoid arthritis synovium. PNAS USA 2002;99:10025-30). On the other hand, high proliferating tissues undergo a wide range of architectural changes and structural rearrangements, and are thereby more prone to experience topological reorganization as well as modification in their biophysical properties. Those alterations may likely be transferred through mechanotrasduction to the cell, where they affect cytoskeleton and nucleoskeleton architecture, as well as many cellular functions. Evidence favoring this view is represented by cells carrying the same gene mutations displaying a very different cancer rate according to the tissues in which those cells are located. For instance, in animal bearing APC-gene mutation, cancers occur mostly in the large intestine rather than in the small intestine, despite having comparable proliferation rates. In other words, the presence of a well-known mutation does not explain cancer onset. How can such paradoxical data be explained?
Undoubtedly, it has become unavoidable to re-evaluate the data collected during a century of cancer research dominated by the premises of the failed SMT and to consider alternative theoretical approaches aimed at explaining carcinogenesis. Such alternative theoretical framework is provided by the Tissue Organization Field Theory (TOFT) originally proposed fifteen years ago by C. Sonnenschein and A. Soto.
Finally, I deem that the consequences of the “bad luck” conclusions drawn by Tomasetti and Vogelstein will end up being worrisome for SMT advocates, an outcome they may not have aimed at. After all, perhaps it is not a matter of ‘bad luck’, but a matter of ‘bad theories’.