Analysis of Somatic Mutations in Cancer Tissues Challenges the Somatic Mutation Theory of Cancer


According to the somatic mutation theory (SMT) of cancer, somatic mutations observed in cancerous tissues directly cause malignancy. However, a close look at the experimental data and observations about human diseases show many discrepancies with the theory, including the lack of specificity of the so‐called ‘cancer genes’ that are mutated in noncancerous tissues, and not mutated in cancers; the rarity of malignancies in some genetic conditions with deoxyribonucleic acid repair anomalies and the high number of initial mutations in early carcinogenesis. Above all, abnormal proliferations and altered tissue architecture before specific genetic anomalies are detected strongly support the idea that the correlation between carcinogenesis and genetic modifications is more complex and probably less determining than has been theorised by the SMT. Other theories that take into account tissue architecture and microenvironment, such as the tissue organisation field theory, are promising paths towards an understanding of oncogenesis.

Key Concepts:

  • Initial somatic mutations are found in cancer tissues much more frequently than expected from a random event.

  • Proliferative and architectural anomalies are observed in organs before genetic anomalies occur.

  • Mutations of the so‐called ‘cancer genes’ are present in noncancerous tissues.

  • Mutations of so‐called ‘cancer genes’ are not present in all cells of a cancer/tumour.

  • Tissues maintain their respective phenotypes despite many mutations.

  • Some conditions with DNA repair deficiency have no increased risk of cancer, and some others appear to be protected against particular cancer types.

  • Cancers can be induced by transplanting a normal tissue into an unusual environment for that tissue.

  • Cancer cells can be reverted to normal cells when implanted into a microenvironment that is normal for this type of cells.

Keywords: somatic mutation; mutation rate; carcinogenesis; somatic mutation theory; tissue organisation field theory; oncogene; tumour suppressor gene; Down syndrome; microenvironment

Figure 1.

Early steps of carcinogenesis at the cell level according to the SMT of cancer and the proposed ‘abnormal function tissue approach’ (AFTA). For the SMT, the first oncogenic event is a somatic mutation on a cancer gene (a), which leads to a preneoplastic state (b). For the AFTA, the early events are cell and tissue (cytoplasmic and/or membranous and/or architectural) modifications (c), which in turn induce genetic modifications such as somatic mutations (d). IM, inducing somatic mutation; AM, adaptative somatic mutation. Indicated in white is normal, in yellow preneoplastic modifications and the red dot indicates a somatic mutation.

Figure 2.

Early steps of carcinogenesis at the tissue level according to the SMT of cancer and according to the proposed ‘abnormal function tissue approach’ (AFTA) of cancer. For the SMT, in a normal tissue (a) appears the first somatic mutation (+) in one cell (b). The cell that has a selective advantage leads to a clone. In one cell of this clone appears a second somatic mutation (c). After, rounds of selection – expansion of clones produced by additional somatic mutations (d) the population becomes neoplastic bearing the mutations that are responsible for the neoplastic state. For the AFTA, in a normal tissue (e) the first preneoplastic modifications occur in the cytoplasm and/or the membrane of many cells, without somatic mutations at this stage, (f) leading to anomalies of proliferation, differentiation, architecture, etc. In a later stage as the neoplastic process progresses adaptative mutations appear in some cells (g). When the population is fully neoplastic some mutations appear as the consequence of the neoplastic state (h). White indicates normal cells; yellow indicates an early preneoplastic state; pink indicates a more advanced neoplastic state and orange indicates full cancer. AFTA is not a theory such as the SMT or the TOFT but an attempt model to understand carcinogenesis, taking into account facts that are definitely contradictory with the SMT.



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Satgé, Daniel(Sep 2013) Analysis of Somatic Mutations in Cancer Tissues Challenges the Somatic Mutation Theory of Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024465]