Genetic and Epigenetic Heterogeneity in Cancer

Abstract

Abstract Cancer is commonly viewed as a disease of the stepwise accumulation of gene mutations. However, genetic and epigenetic heterogeneity (GEH) is pervasive in cancer, playing a key role in promoting cancer progression. GEH occurs at three primary levels, the genome, gene and epigenetic levels and increases during the aging process and during stress. GEH at the genome level plays the largest role of the three in cancer evolution, as genome level change creates new cellular systems whereas genetic and epigenetic level change mainly modify the existing system. This system replacement achieved by genome level change is essential for cancer evolution. GEH challenges traditional molecular‐based cancer research that focuses on common gene mutations in linear models of progression. Clinically, GEH must be monitored in order to determine the evolutionary potential of a tumour. Increased knowledge about GEH will benefit basic research and cancer treatment. Key Concepts: Cancer progression is a typical process of somatic evolution of which system heterogeneity is a key component. Genetic and epigenetic heterogeneity occurs at three levels: the genome level, the gene level and the epigenetic level. The three levels of genetic and epigenetic heterogeneity are highly interactive. Genome level heterogeneity can influence gene and epigenetic level heterogeneity and vice versa. Genetic and epigenetic heterogeneity, especially at the genome level is the key driver of somatic evolution. Genome level change results in macroevolution, which creates new systems, whereas gene and epigenetic level changes result in microevolution which modifies the existing system. The heterogeneity within cancer can lead to the identification of multiple driver pathways, however, each identified pathway reduces the relative contributions of the others to the cancer phenotype within patient populations. This leads to limitations of clinical predictions that are based on individual genes or pathways. Monitoring heterogeneity rather than specific pathways will lead to a better understanding of the evolutionary potential of a tumour and will aid in treatment and diagnosis.