Genetic and epigenetic heterogeneity in cancer: A genome‐centric perspective

Abstract

Genetic and epigenetic heterogeneity (the main form of non-genetic heterogeneity) are key elements in cancer progression and drug resistance, as they provide needed population diversity, complexity, and robustness. Despite drastically increased evidence of multiple levels of heterogeneity in cancer, the general approach has been to eliminate the "noise" of heterogeneity to establish genetic and epigenetic patterns. In particular, the appreciation of new types of epigenetic regulation like non-coding RNA, have led to the hope of solving the mystery of cancer that the current genetic theories seem to be unable to achieve. In this mini-review, we have briefly analyzed a number of mis-conceptions regarding cancer heterogeneity, followed by the re-evaluation of cancer heterogeneity within a framework of the genome-centric concept of evolution. The analysis of the relationship between gene, epigenetic and genome level heterogeneity, and the challenges of measuring heterogeneity among multiple levels have been discussed. Further, we propose that measuring genome level heterogeneity represents an effective strategy in the study of cancer and other types of complex diseases, as emphasis on the pattern of system evolution rather than specific pathways provides a global and synthetic approach. Compared to the degree of heterogeneity, individual molecular pathways will have limited predictability during stochastic cancer evolution where genome dynamics (reflected by karyotypic heterogeneity) will dominate.

Evolutionary mechanism unifies the hallmarks of cancer

“…In contrast to the traditional assumption that genome-level change would be passed on to the daughter cells if the cell divides, for these cells with unstable genomes, parental cells cannot pass on the same genome. 25,32,35,36 This leads to the unique feature of the cancer cell population, where an entire cell population can display different types of genomes.…”

“…31 The evolutionary mechanism of cancer consists of three key components: (i) system stress (biological process itself including metabolic dynamics, aging, bio-system errors, environmental challenges, cellular adaptive processes), (ii) population diversity (at phenotype level, the hallmarks, and their dynamics; at genotype level, there are multiple levels of genetic and non-genetic inheritance which can contribute to the hallmarks in a less predictable fashion), and (iii) genome-mediated macro-cellular evolution (since the genome is the platform that organizes emergent properties and passes system inheritance, genomelevel alteration is the driving force to achieve the evolution of new systems rather than individual features/hallmarks, despite that lower-level genetic changes can influence genome-level changes). 25,35,36 Significantly, such simple framework can solve many wellknown paradoxes in the field. First, various types of genomic and non-genetic variation are not just "genomic errors," but these serve the important biological functions of stress response and short-term adaptation.…”

Insights on processes of evolutionary tumor growth

“…Further, increased efforts to identify common drivers have resulted in massive amounts of varying and conflicting data. Most solid tumors are marked by high degrees of intra-and inter-tumor genome heterogeneity at multiple genetic and non-genetic levels, and this was recently confirmed with highthroughput sequencing (Gerlinger et al, 2012;Heng et al, 2009;Heppner, 1984). The high degrees of heterogeneity characteristic of tumors coupled with a lack of shared driver mutations have posed a challenge to the stepwise concept of cancer evolution (Heng, 2007a;Heng et al, 2013a;Podlaha et al, 2012).…”

“…That is the reason why there are so many different types of nonclonal chromosomal aberrations (NCCAs) detected in various cancers and other diseases (Gisselsson and Hoglund, 2005;Heng et al, 2004;Heng et al, 2013b;Horne et al, 2014a). To make sense of this heterogeneity and better understand tumor growth and cancer progression, a new conceptual framework must be applied in cancer research that accounts for and unifies the molecular diversity of the disease (Heng et al, 2010a;Horne et al, 2014b;Ye et al, 2009). One such framework is the genome theory of cancer evolution (Heng et al, 2006a;Heng et al, 2006b;Heng, 2009).…”

“…To make sense of this heterogeneity and better understand tumor growth and cancer progression, a new conceptual framework must be applied in cancer research that accounts for and unifies the molecular diversity of the disease (Heng et al, 2010a;Horne et al, 2014b;Ye et al, 2009). One such framework is the genome theory of cancer evolution (Heng et al, 2006a;Heng et al, 2006b;Heng, 2009). Herein, we discuss genome-mediated cancer evolution as it pertains to tumor growth.…”