Evolutionary karyotypic theory of cancer versus conventional cancer gene mutation theory

Abstract

For decades the conventional gene mutation cancer theory has been postulating that cancer is a genetic disease considered as a result of deterministic sequential accumulation of mutations in the handful of «driver» cancer genes occurring in a continuous linear pattern of cancer progression. However, in contrast to this postulate, recent whole genome and exome sequencing studies of primary tumor bulk and metastases or separate regions withing the same sample have revealed a large number of stochastic gene mutations for each individual with the same cancer type and significant intratumoral genetic heterogeneity with «branched evolutionary tumor growth» or «punctuated clonal evolution without observable intermediate branching» or «no dominant clones in the cancer tissue». Meanwhile, the stochastic karyotypic variation and intratumor heterogeneity are recognized to be the driving force of tumor evolution and major factors in determining relapse with acquired drug resistance. The karyotype evolution/chromosome instability and the resulting magnitude of intratumor heterogeneity significantly correlate with tumorigenic potential of cells, tumor disease progression from precancerous lesions to malignant tumors and metastases, correlate with patient survival, treatment sensitivity, and the risk of acquired resistance. Here, we discuss importance of the evolutionary karyotypic theory in understanding the cancer biology and mechanisms of tumor drug resistance

New insights into the earliest stages of colorectal tumorigenesis

“…In this model, the first few neoplastic cell divisions leading to the establishment of an adenoma generate many passenger mutations and copy number alterations. This increased evolutionary tempo may be due in part to the process of neoplastic transformation itself and chromosomal missegregation or some other form of genetic instability [37, 38, 39, 40]. Once all the necessary driver mutations are acquired, cancers grow from a single expansion of a diverse population of tumor cells, characterized by neutral evolution instead of Darwinian survival [27, 41, 42, 43].…”

Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)

“…Following meiotic development from mitosis [48], there would still be need for such an ancient system, because of vegetative reproduction, and that meiotic reproduction most often, was/is relegated to specific environmental conditions [49] [50]. Cancer cell proliferation is a form of vegetative reproduction, and by some considered to be a development to cancer genome speciation with "genetic cohesiveness" [11] [51] [52] [53]. This latter feature has been "dramatically" shown by automated, computer-assisted 3D karyotype analyses, revealing cancer clones having specific, "stable" karyotypic phenotypes, others showing "on-going" instability [54] [55].…”

Cancer Genes and Chromosome Instability

“…Illusion of oncogene dependence [199] and limited relevance of oncogene addiction concept for the majority of tumors [211] led to eradication of the hope of targeting the key addictive oncogene that maintains one's cancer [220]. Really, the obvious success of targeted therapy based on oncogene addiction concept is mainly restricted only to chronic myelogenous leukaemia (CML) in clinic [22,223], which possesses in chronic phase, a major phase of drug response, a homogeneous population of tumor cells arisen from a single driver mutation, although still with high frequency of resistance development (35% of patients in chronic phase treated with imatinib) [224,225].…”

“…Limited number of initiating genetic alterations, artificially activated oncogenes, benign levels of CIN, intratumor genetic homogeneity, and fostered evolution make mice tumors inappropriate models for the targeted treatment of cancers [6,50,218,229]. Cancer therapy based on oncogene addiction concept is palliative rather than curative in clinic [22]. Also, the uniqueness and significance of oncogene addiction concept should be questioned by a growing list of non-oncogenes that are not inherently oncogenic themselves (not mutated or altered in any way) but required for tumor initiation and maintenance in a variety of cancer models [230][231][232][233][234].…”

“…It is documented that extreme CIN relative to tumors with intermediate CIN is associated with improved survival outcome in cancer and experimental models have evidenced that extreme CIN has a negative impact on cellular fitness, generating nonneoplastic and nonviable cells, and constrains tumorigenesis. However, CIN represents early and causative event in cancer progression and significantly correlates with tumorigenic potential of cells and such clinical variables as tumor progression from precancerous lesions to malignant tumors and then to metastases, survival, treatment sensitivity, and the risk of acquired therapy resistance (reviewed in [22]). …”