The Heterogeneity of Cancer and DNA as a Prognostic Marker: The Truth is in our Blood

OLYMPUS DIGITAL CAMERATumours are incredibly heterogeneic- that is that they have different properties including morphology (how they look), metabolism (the processes they use to generate energy), proliferation (how fast they grow, divide and replicate themselves) and potential to metastasise (where a tumour moves to another part of the body).  But why is this so?

Many people are under the assumption that a cancer will arise from a single mutation in the DNA, but this is not actually the case.  For a cancer to develop we must first have that single mutation, or “hit”, which may make a cell more likely to receive further mutations.  But in a final tumour mass what we actually find is that different populations of cells have entirely different mutations.  The “clonal evolution” theory explains that this is because the initial few mutations have a cascading effect, allowing further DNA damage, and as these damaged cancerous cells replicate themselves their daughter cells will in turn develop further mutations.

There is another theory as to why this occurs that focuses on cancer stem cells, where a healthy stem cell becomes cancerous and can self-renew and differentiate into its different progeny cells to form a tumour mass, with each subset of cells having different “normal” as well as “cancerous” properties due to the initial mutation coming from a stem cell which has the ability to produce different cell types.  (It’s actually all a bit more complex than this- this article explains things in more detail)

However it happens, this heterogeneity makes developing specific treatments really difficult because you need to target all of the different populations of cells within the tumour (and potentially the original cancerous stem cell), each of which can be radically different (especially if the cancer is not caught early enough).  This makes the act of taking a biopsy from a tumour difficult, as each portion of the tumour you remove to investigate in the lab may be vastly different from cells mere centimetres away.

But what if there was another way to categorise mutations within tumours and to track their growth and the progress of any chemotherapy?  When some of these tumour cells burst and die, they will release the contents of the cell into the bloodstream, including portions of DNA (also termed circulating tumour DNA, or ctDNA).  Some of this will be initially caught by macrophages, immune cells which hoover up the contents of these burst cells, so this DNA only stays in the blood for a number of hours before being degraded.  As such, it is perfect for tracking a patients cancer and treatment, as these “liquid biopsies” yield results that will always be up to date as the DNA will only be present for a short period of time.  As each population within the tumour will have its own DNA mutations, these can be used to visualise a whole picture of the cancer and the DNA damage within it.

Of course, as with any new technology there are currently some set backs to its use.  The ctDNA cannot cross the blood-brain barrier (the barrier that separates the brain from the rest of the body) so cannot be used to characterise brain tumours.  Also, the smaller the tumour the less cancerous cells will burst and the lower the amount of ctDNA in the blood, making it hard to detect at a high enough level.  Detection of the DNA is very expensive and we often don’t know exactly what mutations we are looking for.  But with screening technology becoming more and more advanced (and eventually less and less expensive), this should become less of a problem in the future.

These “liquid biopsies” have huge future applications in cancer therapy, but the technology is actually already being used during pregnancy.  Interestingly, when pregnant, a mother-to-be actually will have some foetus DNA in their blood, allowing us to accurately determine the sex of a baby as well as screening for potentially dangerous disorders without having to harm the child at all.  This was the first practical use for the technology, and is used widely today.

With cancers having the ability to adapt over time, this technology is going to become very important in tracking resistance to therapy, allowing us a real window into personalised therapy, where doctors can tailor treatment to each individual.

Amy

If you want to read more, Ed Yong wrote a fantastic article for nature on the subject

And if you enjoyed this article, you may also like:

 What Makes a Cancer a Cancer- The Hallmarks of Cancer

Weapons Against Cancer- Genetically Engineered T Cells 

Feeling the Heat- The Science of Sunburn

References:

Lo, Y., Corbetta, N., Chamberlain, P., Rai, V., Sargent, I., Redman, C., & Wainscoat, J. (1997). Presence of fetal DNA in maternal plasma and serum The Lancet, 350 (9076), 485-487 DOI: 10.1016/S0140-6736(97)02174-0

Vasioukhin V, Anker P, Maurice P, Lyautey J, Lederrey C, & Stroun M (1994). Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. British journal of haematology, 86 (4), 774-9 PMID: 7918071

An interesting clinical trial where they used this technology- De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CK, Nuciforo P, Bidard FC, Aura C, Saura C, Peg V, Piscuoglio S, Oliveira M, Smolders Y, Patel P, Norton L, Tabernero J, Berger MF, Seoane J, & Reis-Filho JS (2014). Capturing Intra-Tumor Genetic Heterogeneity by De Novo Mutation Profiling of Circulating Cell-Free Tumor DNA: A Proof-of-Principle. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO PMID: 25009010

Pantel K, & Alix-Panabières C (2013). Real-time liquid biopsy in cancer patients: fact or fiction? Cancer research, 73 (21), 6384-8 PMID: 24145355

Image from: http://en.wikipedia.org/wiki/Blood_test#mediaviewer/File:Blood_test.jpg

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3 responses to “The Heterogeneity of Cancer and DNA as a Prognostic Marker: The Truth is in our Blood

  1. This is interesting. If you already answered this question in your blog, would you mind repeating it. How does a mutation arise in the DNA in the first place?

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