Cancer evolution and heterogeneity

Abstract

Undoubtedly, intratumor heterogeneity (ITH) is one of the causes of the intractability of cancers. Recently, technological innovation in genomics has promoted studies on ITH in solid tumors and on the pattern and level of diversity, which varies among malignancies. We profiled the genome in multiple regions of nine colorectal cancer (CRC) cases. The most impressive finding was that in the late phase, a parental clone branched into numerous subclones. We found that minor mutations were dominant in advanced CRC named neutral evolution; that is, driver gene aberrations were observed with high proportion in the early-acquired phase, but low in the late-acquired phase. Then, we validated that neutral evolution could cause ITH in advanced CRC by super-computational analysis. According to the clinical findings, we explored a branching evolutionary process model in cancer evolution, which assumes that each tumor cell has cellular automaton. According to the model, we verified factors to foster ITH with neutral evolution in advanced CRC. In this review, we introduce recent advances in the field of ITH including the general component of ITH, clonal selective factors that consolidate the evolutionary process, and a representative clinical application of ITH.

Keywords: The ratio between the rate of non‐synonymous substitutions per non‐synonymous site and the rate of synonymous substitutions per synonymous site; cellular automaton; intratumor heterogeneity; variant allele frequency; whole‐exome sequencing.

Figure 1

Branching evolutionary process (BEP) model. A, A cell has n genes, d of which are driver genes. In a unit time step, a cell divides and dies with probabilities p and q, respectively. A cell division mutates each gene with a probability r. One driver mutation increases p by f‐fold. In this model, f indicates strength of the driver genes. B, Population entropy depends on parameters d and f. The division probability increases per driver mutation. Red area indicates negentropy or syntropy, whereas white area indicates entropy. C, Existence of strong driver genes leads to a homogenous tumor. D, Multiple driver genes of moderate strength generate intratumor heterogeneity

Figure 2

A, Implementation of environmental selection (n, number of genes; d, number of driver genes). If mutation has occurred in each quadrant of the tumor, selective driver genes increase growth rate. B, Existence of environmental selection can also enhance intratumor heterogeneity, which looks close to the actual heterogenous tumor