Intratumoral Heterogeneity of the Epigenome

Abstract

Investigation into intratumoral heterogeneity (ITH) of the epigenome is in a formative stage. The patterns of tumor evolution inferred from epigenetic ITH and genetic ITH are remarkably similar, suggesting widespread co-dependency of these disparate mechanisms. The biological and clinical relevance of epigenetic ITH are becoming more apparent. Rare tumor cells with unique and reversible epigenetic states may drive drug resistance, and the degree of epigenetic ITH at diagnosis may predict patient outcome. This perspective presents these current concepts and clinical implications of epigenetic ITH, and the experimental and computational techniques at the forefront of ITH exploration.

Figure 1. Inferring the evolutionary history of a tumor from intratumoral heterogeneity

(A) Analysis of spatially distinct biopsies can be used to build a phylogeny which represents the evolutionary history of a tumor. Phylogeny tree branches are colored according to the contributions of each cell population: the black branch contains alterations that are shared amongst all biopsies, the red/blue branch contains alterations shared between the red and blue biopsies and the red, blue and purple branches represents those alterations which are uniquely present in a single biopsy. (B) Phylogenies have traditionally been built from genetic alterations, including somatic mutations and copy number alterations. Phyloepigenetic trees have been built from genome-wide DNA methylation data and could be similarly derived from other epigenetic marks, including histone modification patterns, open chromatin or RNA expression levels. Representative patterns of somatic mutations, copy number alterations and DNA methylation (black = methylated CpG site; white = unmethylated CpG site) are shown. To date, tumor histories derived from genetic alterations and DNA methylation show similar evolutionary patterns, raising the question of the extent to which these alterations are functionally related. Further work is still required to determine if phylogenies derived from histone modifications and RNA expression also reflect similar evolutionary histories.

Figure 2. Clinical implications of intratumoral heterogeneity

(A) Low levels of intratumoral heterogeneity in DNA methylation (mITH) have been associated with improved progression free survival (PFS) and overall survival (OS). (B) Two different timeline models of the relationship between PFS and mITH. A tumor initiates (far left) and expands while acquiring a series of epigenetic alterations leading to three distinct subclones (shades of blue) at the time of surgical resection (vertical black line). In both scenarios, identical subclones are present at initial resection. Surgical resection removes the majority of tumor cells although a small number remain which continue to evolve and eventually develop into the recurrence after a short (top) or long (bottom) period of progression-free survival (PFS). Here we question whether the duration of PFS may correlate with the levels of mITH in the recurrent tumor (cell populations on right). (C) The impact of therapy on mITH is understudied. For a given number of subclones at diagnosis (top), therapy may selectively kill some subclones leading to decreased mITH at recurrence (left), or it may not alter the diversity of subclones, leading to a recurrence with similar subclones as the diagnostic tumor (center), or it may promote increased mITH and expansion of novel subclones leading to a more heterogeneous recurrence (right).