Colorectal Cancer Cells Demonstrate Genetic and Epigenetic Heterogeneity

Clonal selection in cancer is based upon cellular phenotypic characteristics; however, the roles that genetic and epigenetic variation as well as transcriptional plasticity play in intratumoral heterogeneity and tumor evolution have not been fully elucidated. In two complementary studies, Househam, Heide, and colleagues along with Heide, Househam, and colleagues sought to determine how tumor genomes and epigenomes concomitantly evolve and thus shape intratumor genetic and epigenetic heterogeneity in colorectal cancer (CRC), showing that the genetic and epigenetic modifications in cancer-associated genes occur independently, with a majority of this intratumor heterogeneity in gene expression being “plastic.” Househam, Heide, and colleagues indicated, using a spatially resolved, multiomic, single-gland profiling dataset of 297 samples from 27 primary CRCs that were part of the Evolutionary Predictions in CRC study, that most gene expression programs in CRC are plastic and are not uniformly expressed across CRCs, as gene expression programs vary regardless of the accumulated genetic changes present in tumor cells, possibly due to the tumor microenvironment. Additionally, spatially resolved genomics revealed a large portion of CRCs do not exhibit subclonal selection of driver genes, with transcriptional variation existing in selected clones. Comparable outcomes were observed in the study by Heide, Househam, and colleagues in which the use of spatial multiomic profiling of individual glands at the single-clone level from 1,230 samples across 30 primary cancers and eight adenomas demonstrated that DNA mutations in chromatin modifier genes were positively selected with only a few recurrently mutated genes. This group also showed that recurrent somatic chromatin accessibility alterations are high at regulatory regions of driver genes, with most of these being clonal. Moreover, these epigenetic changes were demonstrated as important for tumor evolution and affected transcription factor binding, were heritable, and could distinguish adenomas from cancers. Together, the results of these two studies demonstrate genetic and epigenetic heterogeneity in CRC tumors and suggest that both transcriptional plasticity and nongenetic determinants have a critical function in clonal evolution.

Househam J, Heide T, Cresswell GD, Spiteri I, Kimberley C, Zapata L, et al. Phenotypic plasticity and genetic control in colorectal cancer evolution. Nature 2022;611:744–53.

Heide T, Househam J, Cresswell GD, Spiteri I, Lynn C, Mossner M, et al. The co-evolution of the genome and epigenome in colorectal cancer. Nature 2022;611:733–43.

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