Cancer-causing somatic mutations: they are neither necessary nor sufficient

Carlos Sonnenschein, Ana M. Soto

Abstract


For over a century, the somatic mutation theory of carcinogenesis (SMT) has been adopted by researchers as the theory of record to explain the vast bio-medical implications of the cancer disease. Central to this theory is the notion that mutated alleged cancer genes are responsible for the cancer phenotype(s). Despite generous sustained funding and unwavering research commitments, the presence and the roles of genomic mutations remain undefined and controversial. Our analysis of the merits of causatively linking mutated cancer genes and cancer phenotypes suggests that such mutations are neither necessary nor sufficient.

Full Text:

PDF

References


Acuna-Hidalgo, R, Bo, T, Kwint, MP, van de Vorst, M, Pinelli, M, Veltman, JA, Hoischen, A, Vissers, LE et al. 2015, "Post-zygotic point mutations are an underrecognized source of de novo genomic variation", American Journal of Human Genetics, vol. 97, pp. 67-74.

Alberts, B, Johnson, A, Lewis, J, Morgan, D, Raff, M, Roberts, K & Walter, P 2014, Molecular Biology of the Cell. 6th ed. Garland Science, New York.

Alexandrov, LB, Nik-Zainal, S, Wedge, DC, Aparicio, SA, Behjati, S, Biankin, AV, Bignell, GR, Bolli, N et al. 2013, "Signatures of mutational processes in human cancer", Nature, vol. 500, pp. 415-421.

Anglesio, MS, Papadopoulos, N, Ayhan, A, Nazeran, TM, Noë, M, Horlings, HM, Lum, A, Jones, S et al. 2017, "Cancer-associated mutations in endometriosis without cancer", N Engl J Med, vol. 376, pp. 1835-1848.

Ayala, FJ 1968, "Biology as an autonomous science", American Scientist, vol. 56, pp. 207-221.

Baker, SG 2015, "A cancer theory kerfuffle can lead to new lines of research", J Natl Cancer Inst, vol. 107, p. dju405.

BBC Is the Knowledge Factory Broken? 2018 https://www.bbc.co.uk/programmes/w3csvsy8

Bertolaso, M 2016, Philosophy of Cancer.Springer.

Bishop, JM 1991, "Molecular themes in oncogenesis.", Cell, vol. 64, pp. 235-248.

Bizzarri, M & Cucina, A 2016, "SMT and TOFT: Why and how they are opposite and incompatible paradigms", Acta Biotheor, vol. 64, pp. 221-239.

Boveri, T 1914, Zur Frage der Entstehung Maligner Tumoren.Fischer, Jena.

Brock, A & Huang, S 2017, "Precision oncology: Between vaguely right and precisely wrong", Cancer Research, vol. 77, pp. 6473-6479.

Burrell, RA & Swanton, C 2016, "Re-evaluating clonal dominance in cancer evolution", Trends Cancer, vol. 2, pp. 263-276.

Bussard, KM, Boulanger, CA, Booth, BW, Bruno, RD & Smith, GH 2010, "Reprogramming human cancer cells in the mouse mammary gland",

Cancer Research, vol. 70, pp. 6336-6343.

Cairns, J 1975, "Mutation selection and the natural history of cancer", Nature, vol. 255, pp. 197-200.

Chen, L, Jenjaroenpun, P, Pillai, AM, Ivshina, AV, Ow, GS, Efthimios, M, Zhigun, T, Tan, TZ et al. 2017, "Transposon insertional mutagenesis in mice identifies human breast cancer susceptibility genes and signatures for stratification", Proceedings of the National Academy of Science of the United States of America, vol. 114, p. E2215-E2224.

Cohen, JD, Li, L, Wang, Y, Thoburn, C, Afsari, B, Danilova, L, Douville, C, Javed, AA et al. 2018, "Detection and localization of surgically resectable cancers with a multi-analyte blood test", Science, vol. 359, pp. 926-930.

Dal, GM, Ergüner, B, Sagiroglu, MS, Yüksel, B, Onat, OE, Alkan, C & Özçelik, T 2014, "Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair", J Med Genet, vol. 51, pp. 455-459.

Drost, J, van Boxtel, R, Blokzijl, F, Mizutani, T, Sasaki, N, Sasselli, V, de Ligt, J, Behjati, S et al. 2017, "Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer", Science, vol. 358, pp. 234-238.

Gatenby, R 2017, "Is the genetic paradigm of cancer complete?", Radiology, vol. 284, pp. 1-3.

Gilbert, SF & Sarkar, S 2000, "Embracing complexity: Organicism for the 21st century", Developmental Dynamics, vol. 219, pp. 1-9.

Gomez-Marin, A 2017, "Causal circuit explanations of behavior: Are necessity an sufficiency necessary and sufficient?", in: Decoding Neural Circuit Structure and Function: Cellular Dissection Using Genetic Model Organisms Çelik, A., Wernet, M.F., (Eds.), Cham:Springer International Publishing AG, pp. 283-307.

Hanahan, D 2014, "Rethinking the war on cancer", Lancet, vol. 383, pp. 558-563.

Heim, S & Mitelman, F 1987, Cancer Cytogenetics.A R Liss, New York.

Hendrix, MJ, Seftor, EA, Seftor, RE, Kasemeier-Kulesa, J, Kulesa, PM & Postovit, LM 2007, "Reprogramming metastatic tumour cells with embryonic microenvironments", Nature Reviews: Cancer, vol. 7, pp. 246-255.

Huang, S 2014, "The war on cancer: lessons from the war on terror", Front Oncol, vol. 4, p. 293.

Jaiswal, S, Fontanillas, P, Flannick, J, Manning, A, Grauman, PV, Mar, BG, Lindsley, RC, Mermel, CH et al. 2014, "Age-related clonal hematopoiesis associated with adverse outcomes", N Engl J Med, vol. 371, pp. 2488-2498.

Jamshidi, N, Margolis, DJ, Raman, S, Huang, J, Reiter, RE & Kuo, MD 2017, "Multiregional radiogenomic assessment of prostate microenvironments with multiparametric MR imaging and DNA whole-exome sequencing of prostate glands with adenocarcinoma", Radiology, vol. 284, pp. 109-119.

Joyner, MJ, Paneth, N & Ioannidis, JP 2016, "What happens when underperforming big ideas in research become entrenched?", Journal of the American Medical Association, vol. 316, pp. 1355-1356.

Ju, YS, Martincorena, I, Gerstung, M, Petljak, M, Alexandrov, LB, Rahbari, R, Wedge, DC, Davies, HR et al. 2017, "Somatic mutations reveal asymmetric cellular dynamics in the early human embryo", Nature, vol. 543, pp. 714-718.

Kalinich, M & Haber, DA 2018, "Cancer detection: Seeking signals in blood.", Science, vol. 359, pp. 866-867.

Kato, S, Lippman, SM, Flaherty, KT & Kurzrock, R 2016, "The conundrum of genetic "drivers" in benign conditions", Journal of the National Cancer Institute, vol. 108, p. pii:djw036.

Krimmel, JD, Schmitt, MW, Harrell, MI, Agnew, KJ, Kennedy, SR, Emond, MJ, Loeb, LA, Swisher, EM et al. 2016, "Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues", Proceedings of the National Academy of Science of the United States of America, vol. 113, pp. 6005-6010.

Lazebnik, Y 2010, "What are the hallmarks of cancer?", Nature Reviews: Cancer, vol. 10, pp. 232-233.

Ledford, H 2017, "Century-old tumours offer rare cancer clues", Nature, vol. 545, p. 278.

Lloyd, MC, Cunningham, JJ, Bui, MM, Gillies, RJ, Brown, JS & Gatenby, RA 2016, "Darwinian dynamics of intratumoral heterogeneity: Not solely random mutations but also variable environmental selection forces", Cancer Research, vol. 76, pp. 3136-3144.

Longo, G, Miquel, P-A, Sonnenschein, C & Soto, AM 2012, "Is information a proper observable for biological organization?", Prog Biophys Mol Biol, vol. 109, pp. 108-14.

Longo, G, Montévil, M, Sonnenschein, C & Soto, AM 2015, "In search of principles for a theory of organisms", Journal of Biosciences, vol. 40, pp. 955-968.

Longo, G & Soto, AM 2016, "Why do we need theories?", Prog Biophys Mol Biol, vol. 122, pp. 4-10.

Lupski, JR 2013, "Genetics. Genome mosaicism-One human, multiple genomes", Science, vol. 341, pp. 358-359.

Macilwain, C 2015, "Change the cancer conversation", Nature, vol. 520, p. 7.

Mack, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stutz, AM, Wang, X, Gallo, M et al. 2014, "Epigenomic alterations define lethal CIMP-positive ependymomas of infancy", Nature, vol. 506, pp. 445-450.

Maffini, MV, Calabro, JM, Soto, AM & Sonnenschein, C 2005, "Stromal regulation of neoplastic development: Age-dependent normalization of neoplastic mammary cells by mammary stroma", American Journal of Pathology, vol. 167, pp. 1405-1410.

Maffini, MV, Soto, AM, Calabro, JM, Ucci, AA & Sonnenschein, C 2004, "The stroma as a crucial target in rat mammary gland carcinogenesis", Journal of Cell Science, vol. 117, pp. 1495-1502.

Martincorena, I & Campbell, PJ 2015, "Somatic mutation in cancer and normal cells", Science, vol. 349, pp. 1483-1489.

May M Tumor Mutation Burden: Unlocking Cancer's Genetic Fingerprint 2018 https://www.scientificamerican.com/custom-media/tumor-mutation-burden/

McConnell, MJ, Moran, JV, Abyzov, A, Akbarian, S, Bae, T, Cortes-Ciriano, I, Erwin, JA, Fasching, L et al. 2017, "Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network", Science, vol. 356, p. 6336.

McCullough, KD, Coleman, WB, Ricketts, SL, Wilson, JW, Smith, GJ & Grisham, JW 1998, "Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors", Proceedings of the National Academy of Science of the United States of America, vol. 95, pp. 15333-15338.

McKerrell, T, Park, N, Moreno, T, Grove, CS, Ponstingl, H, Stephens, J, Understanding Society Scientific Group, Crawley, C et al. 2015, "Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis", Cell Rep, vol. 10, pp. 1239-1245.

Merlo, LM, Pepper, JW, Reid, BJ & Maley, CC 2006, "Cancer as an evolutionary and ecological process", Nature Reviews: Cancer, vol. 6, pp. 924-935.

Mintz, B & Ilmensee, K 1975, "Normal genetically mosaic mice produced from malignant teratocarcinoma cells", Proceedings of the National Academy of Science of the United States of America, vol. 72, pp. 3585-3589.

Montévil, M & Pocheville, A 2017, "The hitchhiker's guide to the cancer galaxy. How two critics missed their destination", Organisms, vol. 1, pp. 37-48.

Nowell, PC 1976, "The clonal evolution of tumor cell populations", Science, vol. 194, pp. 123-128.

Parker, M, Mohankumar, KM, Punchihewa, C, Weinlich, R, Dalton, JD, Li, Y, Lee, R, Tatevossian, RG et al. 2014, "C11orf95-RELA fusions drive oncogenic NF-kB signalling in ependymoma", Nature, vol. 506, pp. 451-455.

Prasad, V, Kaestner, V & Mailankody, S 2018, "Cancer drugs approved based on biomarkers and not tumor type-FDA approval of pembrolizumab for mismatch repair-deficient solid cancers", JAMA Oncol, vol. 4, pp. 157-158.

Prehn, RT 1994, "Cancers beget mutations versus mutations beget cancers", Cancer Research, vol. 54, pp. 5296-5300.

Roerink, SF, Sasaki, N, Lee-Six, H, Young, MD, Alexandrov, LB, Behjati, S, Mitchell, TJ, Grossmann, S et al. 2018, "Intra-tumour diversification in colorectal cancer at the single-cell level", Nature, vol. 556, pp. 457-462.

Rowley, JD & Mitelman, F 1993, "Principles of Molecular Cell Biology of Cancer: Chromosome Abnormalities in Human Cancer and Leukemia", in: Cancer: Principles & Practice of Oncology DeVita, V.T., Hellman, S., Rosenberg, S.A., (Eds.), Philadelphia:J.B. Lippincott Company, pp. 67-91.

Sansregret, L & Swanton, C 2017, "The Role of aneuploidy in cancer evolution", Cold Spring Harb Perspect Med, vol. 7, p. a028373.

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

-----2017, "Why is it that despite signed capitulations, the war on cancer is still on?", Organisms, vol. 1, pp. 45-52.

Soto, AM, Longo, G, Montévil, M & Sonnenschein, C 2016, "The biological default state of cell proliferation with variation and motility, a fundamental principle for a theory of organisms", Prog Biophys Mol Biol, vol. 122, pp. 16-23.

Soto, AM & Sonnenschein, C 2011, "The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory", BioEssays, vol. 33, pp. 332-340.

Stratton, MR, Campbell, PJ & Futreal, PA 2009, "The cancer genome", Nature, vol. 458, pp. 719-724.

Tannock, IF & Hickman, JA 2016, "Limits to personalized cancer medicine", N Engl J Med, vol. 375, pp. 1289-1294.

Taylor, AM, Shih, J, Ha, G, Gao, GF, Zhang, X, Berger, AC, Schumacher, SE, Wang, C et al. 2018, "Genomic and functional approaches to understanding cancer aneuploidy", Cancer Cell, vol. 33, pp. 676-689.

Tomasetti, C, Li, L & Vogelstein, B 2017, "Stem cell divi-sions, somatic mutations, cancer etiology, and cancer prevention", Science, vol. 355, pp. 1330-1334.

Triolo, VA 1965, "Nineteenth century foundations of cancer research advances in tumor pathology, nomenclature, and theories of oncogenesis", Cancer Research, vol. 25, pp. 76-98.

Vaux, DL 2011, "In defense of the somatic mutation theo-ry of cancer", BioEssays, vol. 33, pp. 341-343.

Versteeg, R 2014, "Cancer: Tumours outside the mutation box", Nature, vol. 506, pp. 438-439.

Vogelstein, B, Papadopoulos, N, Velculescu, VE, Zhou, S, Diaz, LA, Jr. & Kinzler, KW 2013, "Cancer genome landscapes", Science, vol. 339, pp. 1546-1558.

Weaver, BA & Cleveland, DW 2006, "Does aneuploidy cause cancer?", Current Opinion in Cell Biology, vol. 18, pp. 658-667.

Weinberg, RA 1998, One renegade cell: how cancer be-gins.Basic Books, New York.

-----2014a, "Coming full circle-from endless complexity to simplicity and back again", Cell, vol. 157, pp. 267-271.

-----2014b, The Biology of Cancer. 2nd ed. Garland Science, New York.

Yadav, VK, DeGregori, J & De, S 2016, "The landscape of somatic mutations in protein coding genes in apparently benign human tissues carries signatures of relaxed purifying selection", Nucleic Acids Research, vol. 44, pp. 2075-2084.

Yaffe, MB 2013, "The scientific drunk and the lamppost: massive sequencing efforts in cancer discovery and treatment", Sci Signal, vol. 6, p. pe13.

Ye, X & Weinberg, RA 2015, "Epithelial-mesenchymal plasticity: A central regulator of cancer progression", Trends Cell Biol, vol. 25, pp. 675-686.




DOI: https://doi.org/10.13133/2532-5876_3.12

Refbacks

  • There are currently no refbacks.









Organisms. Journal of Biological Sciences
ISSN 2532-5876