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

Abstract

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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References

Abouzeid H , Schorderet DF , Balmer A and Munier FL (2009) Germline mutations in retinoma patients: relevance to low‐penetrance and low‐expressivity molecular basis. Molecular Vision 15: 771–777.

Ahmed M , Sternberg A , Hall G et al. (2004) Natural history of GATA1 mutations in Down syndrome. Blood 103: 2480–2489.

Araten DJ , Golde DW , Zhang RH et al. (2005) A quantitative measurement of the human somatic mutation rate. Cancer Research 65: 8111–8117.

Arlett CF and Lehmann AR (2004) Xeroderma pygmentosum, Cockayne syndrome and trichothio dystrophy: Sun sensitivity, DNA repair defects and skin cancer. In: Eeles RA , Easton DF , Ponder BAJ and Eng C (eds) Genetic Predisposition to Cancer, 2nd edn, pp 214–231. London: Arnold.

Baisse B , Bouzourene H , Saraga EP , Bosman FT and Benhattar J (2001) Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma. International Journal of Cancer 93: 346–352.

Baker SG (2012) Paradoxes in carcinogenesis should spur new avenues of research: an historical perspective. Disruptive Science and Technology 1: 100–107.

Bénard J , Béron‐Gaillard N and Satgé D (2005) Down's syndrome protects against breast cancer: is a constitutional cell microenvironment the key? International Journal of Cancer 113: 168–170.

Biskind MS and Biskind GS (1944) Development of tumors in the rat ovary after transplantation in the spleen. Proceedings of the Society of Experimental Medicine 55: 176–181.

Boros M , Marian C , Moldovan C and Stolnicu S (2012) Morphological heterogeneity of the simultaneous ipsilateral invasive tumor foci in breast carcinoma: a retrospective study of 418 cases of carcinomas. Pathology Research and Practice 208(10): 604–609.

Brash D and Cairns J (2009) The mysterious steps in carcinogenesis. British Journal of Cancer 101: 379–380.

Duesberg P and Rasnick D (2000) Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motility and Cytoskeleton 47: 81–107.

Farber E and Rubin H (1991) Cellular adaptation in the origin and development of cancer. Cancer Research 51: 2751–2761.

Feinberg AP and Coffey DS (1982) Organ site specificity for cancer in chromosomal instability disorders. Cancer Research 42: 3252–3254.

Finette BA , Rood B , Poseno T et al. (1998) Atypical background somatic mutant frequencies at the HPRT locus in children and adults with Down syndrome. Mutation Research 403: 35–43.

Greenman C , Stephens P , Smith R et al. (2007) Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70.

Hernández JL , Rodríguez‐Parets JO , Valero JM et al. (2010) High‐resolution genome‐wide analysis of chromosomal alterations in elastofibroma. Virchows Archives 456: 681–687.

Jozwiak J , Jozwiak S and Wlodarski P (2008) Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncology 9: 73–79.

Klaunig JE , Wang Z , Pu X and Zhou S (2011) Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicology and Appied Pharmacology 254: 86–99.

Knudson AG (1973) Mutation and human cancer. Advances in Cancer Research 17: 317–352.

Konishi N , Hiasa Y , Matsuda H et al. (1995) Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma. American Journal of Pathology 147: 1112–1122.

Lenski RE (1989) Are some mutations directed? Trends in Ecology and Evolution 4: 148–150.

Lijinsky W (1989) A view of the relation between carcinogenesis and mutagenesis. Environmental Molecular Mutagenesis 14(suppl. 16): 78–84.

Maffini MV , Calabro JM , Soto AM and Sonnenschein C (2005) Stromal regulation of neoplastic development: age‐dependent normalization of neoplastic mammary cells by mammary stroma. American Journal of Pathology 167: 1405–1410.

McCullough KD , Coleman WB , Smith GJ and Grisham JW (1997) Age‐dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Research 57: 1807–1813.

Mintz B and Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proceeding of the National Academy of Sciences of the USA 72: 3585–3589.

Ogasawara N , Tsukamoto T , Inada K et al. (2005) Frequent c‐Kit gene mutations not only in gastrointestinal stromal tumors but also in interstitial cells of Cajal in surrounding normal mucosa. Cancer Letters 230: 199–210.

Park SH , Maeda T , Mohapatra G et al. (1995) Heterogeneity, polyploidy, aneusomy, and 9p deletion in human glioblastoma multiforme. Cancer Genetics and Cytogenetics 83: 127–135.

Parsons BL (2008) Many different tumor types have polyclonal tumor origin: evidence and implications. Mutation Research 659: 232–247.

Rastrick JM , Fitzgerald PH and Gunz FW (1968) Direct evidence for presence of Ph‐1 chromosome in erythroid cells. British Medical Journal 1: 96–98.

Rowley JD (1984) Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Research 44: 3159–3168.

Rubin H (2006) What keeps cells in tissues behaving normally in the face of myriad mutations? Bioessays 28: 515–524.

Rubin JB (2009) Only in congenial soil: the microenvironment in brain tumorigenesis. Brain Patholgy 19: 144–149.

Satgé D and Bénard J (2008) Carcinogenesis in Down syndrome: what can be learned from trisomy 21? Seminars in Cancer Biology 18: 365–371.

Satgé D , Lacombe D , Vekemans MJJ et al. (2006) A survey of ocular tumors in Down syndrome alone, or associated with another genetic affection. International Journal on Disability and Human Development 5: 311–317.

Satgé D , Sommelet D , Geneix A et al. (1998) A tumor profile in Down syndrome. American Journal of Medical Genetics 78: 207–216.

Schoemaker MJ , Swerdlow AJ , Higgins CD , Wright AF and Jacobs PA (2008) UK Clinical Cytogenetics Group. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncology 9: 239–246.

Schüler F , Dölken L , Hirt C et al. (2009) Prevalence and frequency of circulating t(14;18)‐MBR translocation carrying cells in healthy individuals. International Journal of Cancer 124: 958–963.

Sonnenschein C and Soto AM (2008) Theories of carcinogenesis: an emerging perspective. Seminars in Cancer Biology 18: 372–377.

Soto AM and Sonnenschein C (2011) The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays 33: 332–340.

Stevens LC (1970) The development of transplantable teratocarcinomas from intratesticular grafts of pre‐ and postimplantation mouse embryos. Developmental Biology 21: 364–382.

Stiller CA (2004) Epidemiology and genetics of childhood cancer. Oncogene 23: 6429–6444.

Szöllösi J , Balázs M , Feuerstein BG , Benz CC and Waldman FM (1995) ERBB‐2 (HER2/neu) gene copy number, p185HER‐2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Research 55: 5400–5407.

Thirlwell C , Will OC , Domingo E et al. (2010) Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. Gastroenterology 138: 1441–1454.

Toth G , Zraly CB , Thomson TL et al. (2011) Congenital anomalies and rhabdoid tumor associated with 22q11 germline deletion and somatic inactivation of the SMARCB1 tumor suppressor. Genes Chromosomes and Cancer 50: 379–388.

Tunstall‐Pedoe O , Roy A , Karadimitris A et al. (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112: 4507–4511.

Vogelstein B and Kinzler KW (2004) Cancer genes and the pathways they control. Nature Medicine 10: 789–799.

Washington C , Dalbègue F , Abreo F , Taubenberger JK and Lichy JH (2000) Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas. American Journal of Pathology 157: 323–329.

Weinberg RA (2007) Maintenance of genomic integrity and development of cancer. In: The Biology of Cancer, pp 39–43, pp 463–526. New York: Garland Science.

Yamanishi Y , Boyle DL , Rosengren S et al. (2002) Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the USA 99: 10025–10030.

Zerbini C , Weinberg DS , Hollister KA and Perez-Atayde AR (1992) DNA ploidy abnormalities in the liver of children with hereditary tyrosinemia type I. Correlation with histopathologic features. American Journal of Pathology 140: 1111–1119.

Zhang L , Zhou W , Velculescu VE et al. (1997) Gene expression profiles in normal and cancer cells. Science 276: 1268–1272.

Further Reading

Baker SG , Cappuccio A and Potter JD (2010) Research on early‐stage carcinogenesis: are we approaching paradigm instability? Journal of Clinical Oncology 28: 3215–3218.

Bizzarri M , Cucina A , Conti F and D'Anselmi F (2008) Beyond the oncogene paradigm: understanding complexity in cancerogenesis. Acta Biotheoretica 56: 173–196.

Cairns J (1981) The origin of human cancers. Nature 289: 353–357.

Capp JP (2012) Nouveau regard sur le cancer. Paris: Belin.

Noble D (2006) The Music of Life. Oxford: Oxford University Press.

Prehn RT (1994) Cancers beget mutations versus mutations beget cancers. Cancer Research 54: 5296–5300.

Sonnenschein C and Soto AM (1999) The Society of Cells: Cancer and Control of Cell Proliferation. New York: Springer Verlag.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0024465]