Heterogenous tumors have different biological, morphological, phenotypic and genotypic profiles. Most, but not all, cancerous tumors display some heterogeneity – it is one of the defining features of cancer.
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Some of the types of tumor heterogeneity
Why heterogeneity can affect cancer treatment
How heterogeneity is linked to treatment resistance
In this infographic, we will explain what tumor
heterogeneity means, explore its different types and
describe its consequences for cancer treatment and
describes the diversity of tumors – this
can be within a tumor, within a patient
or between different patients with the
Heterogeneity can be seen in
describes how similar tumors are to
Heterogenous tumors have different biological, morphological, phenotypic and genotypic
profiles. Most, but not all, cancerous tumors display some heterogeneity – it is one of the
defining features of cancer.
Tumors typically become more heterogenous over time as they accumulate mutations due to
genetic instability and as they are treated with different therapies.
genetics epigenetics protein
(such as single nucleotide
variants or copy number
(DNA methylation and
The uneven distribution of diverse tumor cell
populations. This can arise due to different
influences from the tumor environment at different
sites across a tumor, or between individual tumors
at distant sites in the body. These influences
include the interplay between cancer cells and
surrounding tissue or the immune system, and
outside factors such as the availability of blood
supply, oxygen and nutrients.
Variations in a single tumor over time
due to natural progression or therapeutic
interventions. Involves dynamic
variation over time, for example, across
cancer initiation, progression and
metastasis. It often arises due to targeted
treatments (which creates selection
pressure) or genetic instability.
Treatment & disease progression
What are the
different types of
Tumor heterogeneity can be separated into several types:
How can we
Heterogeneity can affect the discovery of biomarkers – molecules that indicate a
particular characteristic – as well as the effectiveness of some treatments.
Heterogeneity makes it difficult to design effective treatments or to eliminate all
cancer cells. Drugs can target specific mutations identified in a tumor that drive its
growth – usually the dominant clones.
Therapies are a selection pressure – as the sensitive cells are eliminated, non-dominant
clones expand and repopulate the tumor.
Heterogeneity is one of the main barriers to successful therapies, and understanding
its complexity is an ongoing challenge.
Here are some examples of techniques by which we can characterize tumor
Tissue biopsies are the gold standard for clinical
Multiregion sampling involves gathering samples from
multiple regions around a tumor, capturing a more
accurate representation of spatial heterogeneity across
a tumor, unlike core biopsies that sample only small
regions and are likely less informative.
However, multiple biopsies are impractical as they are
very invasive and metastases can be difficult to access.
Less invasive than tissue biopsies, liquid biopsies can be
performed on blood samples.
Blood-based liquid biopsies capture circulating tumor
DNA (ctDNA) shed by tumor cells, which can reveal
both spatial and temporal heterogeneity, and can
capture examples of heterogeneity that single-tumor
biopsies may miss.
Includes histopathology, immunohistochemistry and
fluorescence in situ hybridization (FISH) of tumor tissue.
FISH detects the amplification or deletion of specific
regions of chromosomes and can be used to focus on
specific tumor cells.
Such as whole-exome sequencing (all protein-coding
regions) or whole-genome sequencing (coding and noncoding regions).
These focus on large areas of the genome instead of
particular loci and are more suitable for discovering new
biomarkers. They can also detect differences missed by
focused approaches but can suffer from low resolution.
For example, single-cell RNA or DNA sequencing.
These techniques are some of the most reliable and
enable the study of cellular populations at a greater
This explains why not all patients respond to treatment or why those that initially
responded well eventually relapse, often with new tumors that no longer respond to
Issues surrounding heterogeneity in the clinic have emerged with the development of
targeted therapies. Combining therapies that target the pre-dominant sensitive clones,
as well as subsets of drug-resistant clones, are likely to have the most durable responses.
Overall, heterogeneity fuels resistance and is linked to unfavorable outcomes. Cancers
typically become more heterogeneous and complex with successive treatment
exposures, which have worse responses than initial treatments.
These tumors feature distinct
populations of tumor cells with
varying genetic, epigenetic and
A type of “intrapatient”
This may explain, in part,
why some successfully treated
patients relapse, often with
tumors that no longer respond
to the original therapy.
Where individual tumors of
the same type differ within the
same patient – another type of
This can arise from the
original tumor spreading, with
metastases stemming from the
different “clones” featuring
their respective characteristics.
Established metastases can also
evolve independently from one
This can lead to different
acquired resistance mechanisms
existing in the same patient.
Where patients with the same
cancer type have tumors that
are not clinically similar.
Patients with different tumor
subtypes can have different
biological behaviors and
therefore very different
This can arise due to exposure
to different microenvironments
around the tumor, germline
variants (that are passed from
parent to child) or unique
mutations within tumors
Heterogeneity is also linked to worse responses to
treatments and unfavorable outcomes for patients.
Let’s explore these concepts in more detail.
Survival of resistant clone Repopulation of the tumor
Homogeneous tumor Tumor cells are eliminated
Response to therapy
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