Speciation Theory of Carcinogenesis Explains Karyotypic Individuality and Long Latencies of Cancers

Abstract

It has been known for over 100 years that cancers have individual karyotypes and arise only years to decades after initiating carcinogens. However, there is still no coherent theory to explain these definitive characteristics of cancer. The prevailing mutation theory holds that cancers are late because the primary cell must accumulate 3–8 causative mutations to become carcinogenic and that mutations, which induce chromosomal instability (CIN), generate the individual karyotypes of cancers. However, since there is still no proven set of mutations that transforms a normal to a cancer cell, we have recently advanced the theory that carcinogenesis is a form of speciation. This theory predicts carcinogens initiate cancer by inducing aneuploidy, which automatically unbalances thousands of genes and thus catalyzes chain-reactions of progressive aneuploidizations. Over time, these aneuploidizations have two endpoints, either non-viable karyotypes or very rarely karyotypes of new autonomous and immortal cancers. Cancer karyotypes are immortalized despite destabilizing congenital aneuploidy by clonal selections for autonomy—similar to those of conventional species. This theory predicts that the very low probability of converting the karyotype of a normal cell to that of a new autonomous cancer species by random aneuploidizations is the reason for the karyotypic individuality of new cancers and for the long latencies from carcinogens to cancers. In testing this theory, we observed: (1) Addition of mutagenic and non-mutagenic carcinogens to normal human and rat cells generated progressive aneuploidizations months before neoplastic transformation. (2) Sub-cloning of a neoplastic rat clone revealed heritable individual karyotypes, rather than the non-heritable karyotypes predicted by the CIN theory. (3) Analyses of neoplastic and preneoplastic karyotypes unexpectedly identified karyotypes with sets of 3–12 new marker chromosomes without detectable intermediates, consistent with single-step origins. We conclude that the speciation theory explains logically the long latencies from carcinogen exposure and the individuality of cancers. In addition, the theory supports the single-step origins of cancers, because karyotypic autonomy is all-or-nothing. Accordingly, we propose that preneoplastic aneuploidy and clonal neoplastic karyotypes provide more reliable therapeutic indications than current analyses of thousands of mutations.

Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research

“…Ever since an abnormal number of chromosomes was observed in cancer cells in 1875 [43][44][45] and had later, during the turn from the 19 th to 20 th centuries, been propounded by Hansemann and Boveri as a cancer cause [44,[46][47][48][49][50], the idea that formation and progression of cancer are attributed to mutations has gradually become the orthodox doctrine of carcinogenesis research [51][52][53][54][55][56][57]. With accumulation of clinical and experimental evidence, Nordling formally proffered the first mutation theory of carcinogenesis in 1952 (published in 1953) [58] and, since then, there have been many discourses on the causal relations of various types of mutations to tumorigenesis or carcinogenesis, which are herein referred collectively to as "mutation theory".…”

“…There are some cancers in which no recurrent mutations could be identified [161,162], and there has not been any proven set of mutations known to transform a normal cell to a cancerous one [163]. More bewilderingly, there are some oncogenic driver mutations appearing in benign diseases at a high frequency, sometimes even much higher than in malignant tumors [164][165][166].…”

Reconstructing and counting genomic fragments through tagmentation-based haploid phasing

“…It has been postulated that gene copy number variation is a result of a cellular response intended to increase survivability under stress inducing conditions. Such copy number changes can either promote survival of the cell under adverse conditions, or can induce abnormal behavior resulting in carcinogenesis, metastasis, or drug resistance 2 – 6 . The dynamics and heterogeneity of genomic copy number changes in response to adverse stresses has been the focus of many investigations to elucidate the forces that shape genomes in eukaryotic cells and likely influence karyotypic evolution in cancer cells 4 – 7 .…”

Color Doppler Evaluation of Isovolumetric Relaxation Time and of Signals Arising from Axons of the Median Nerve as a Means to Evaluate Mitochondrial Functionality in the Context of Immunotherapy of Cancer and Chronic Conditions Associated with Mitochondrial Dysfunction

“…When prolonged mitochondrial damage is of such an extent that production of ROS exceeds the capacity of DNA repair mechanisms, random mutations occur with the risk of inducing aneuploidy, a condition that leads to the imbalance of thousands of genes at a time. Such an occurrence leads to genetic and epigenetic chain reactions that either lead to non-viable karyotypes, or in relatively rare cases that develop over time, to immortal cancer cells in a process that resembles speciation (Hirpara et al, 2018). Chemicals or physical treatments such as ionizing radiations, that are defined mutagens for their ability to interact with DNA, are also known disruptors of mitochondrial respiration; defective mitochondrial respiration associated with compensatory fermentation is then responsible for the deluge of mutations that culminate in aneuploidy and, ultimately, in speciation (Seyfried, 2015;Hirpara et al, 2018).…”

“…Such an occurrence leads to genetic and epigenetic chain reactions that either lead to non-viable karyotypes, or in relatively rare cases that develop over time, to immortal cancer cells in a process that resembles speciation (Hirpara et al, 2018). Chemicals or physical treatments such as ionizing radiations, that are defined mutagens for their ability to interact with DNA, are also known disruptors of mitochondrial respiration; defective mitochondrial respiration associated with compensatory fermentation is then responsible for the deluge of mutations that culminate in aneuploidy and, ultimately, in speciation (Seyfried, 2015;Hirpara et al, 2018). Pervasive genetic and epigenetic instability culminating in aneuploidy and speciation further disrupts mitochondrial respiration up to the point that the process becomes autonomous and self-sustaining.…”