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Figure 2. Origin of ITH. Upon certain oncogenic hits, some cells in the normal tissues undergo genetic alterations to generate cancer cells.
ITH arises through clonal evolution in which cells are dictated by transcriptomic and epigenetic factors and the tumor microenvironment.
Cancer clones (yellow) propagate and generate successive clones (green) which outcompete the ancestral ones

ORIGIN OF ITH
[5]
ITH was first described by Fidler et al. more than 30 years ago in murine models as a single tumor consist-
ing of many cell subpopulations. However, this concept of heterogeneity in the composition of a tumor has
now been expanded to include the genetic and molecular heterogeneity present within individual tumor
[6-9]
cells and cells comprising the tumor microenvironment .

Genetic and epigenetic alterations
ITH arises as a result of both genetic and non-genetic changes in the tumor cells and the surrounding en-
[10]
vironment respectively [Figure 2] . Increased genetic instability as a result of mutations in DNA damage
checkpoint control genes and DNA repair genes is one of the hallmarks of cancer and generates divergent
clonal population of cells as the tumor grows over time [11,12] . With the significantly high rate of cancer cell
divisions, events of random mutagenesis increase, leading to local and global genetic alterations, that influ-
[13]
ence the future course of tumor development and progression . In addition, these genetic alterations create
a hotbed for competition between clones driven by selection processes imposed by changes in the tumor mi-
croenvironment and by the use of therapies [14,15] .

A vast majority of established driver mutations are clonal and arise early in the development of the tumor,
however, subclonal de novo driver mutations may also arise in the later stages of tumorigenesis - to escape
[16]
drug sensitivity and successful metastasis, for example . In a recent UK-wide multi-center prospective lon-
gitudinal cohort study, “Tracking Renal Cell Cancer Evolution through therapy (TRACERx Renal)”, clonal
phylogeny and evolutionary subtypes were elucidated by multi-region sampling on matched primary and
[17]
metastasis biopsies from 100 renal cell carcinoma patients . Subclonal driver mutations in the VHL and
PBRM1 genes that were identified in the original tumor were absent in the widely disseminated metastatic
tumor sites. Instead, these metastatic sites acquired loss of 9p and 14q mutations, suggesting that metastatic
[17]
competence may not be driven by the founder driver mutations that established the primary tumor .
Tumor heterogeneity can also arise from epigenetic variations through DNA methylation that can profound-
ly modulate the open and closed conformation of chromatin in tumor cells, leading to gene expression al-
terations and phenotypic changes . For example, the methylation status of the tumor suppressor gene CD-
[18]
[19]
KN2B can be used as a biomarker of response to treatment in multiple diseases . However, heterogeneous
methylation was observed in individual patients with acute myeloid leukemia, posing a challenge in using
[20]
CDKN2B methylation as a biomarker . Similarly, differential microRNA expression is known to affect the
[21]
diversity of cellular phenotype within a single tumor by modulating the expression of target genes . Sub-
clonal expression of microRNAs (miRNA-21, miRNA-34a, miRNA-125, and miRNA-126) in prostate cancer
[22]
is associated with diverse patient outcomes .