Sticky Cancer Genes

 

In the previous blog I talked about Breath Biopsy — a new method that aims to detect cancers from breath samples. I noted that it could end up complementing liquid biopsies — samples of tumour cell DNA pulled out of a teaspoon of blood — both being, as near as makes no difference, non-invasive tests. Just to show that there’s no limit to the ingenuity of scientists, yet another approach to the detection problem has just been published — this from Matt Trau and his wonderful team at The University of Queensland.

This new method, like the liquid biopsy, detects DNA but, rather than the sequence of bases, it identifies an epigenetic profile — that is, the pattern of chemical tags (methyl groups) attached to bases. As we noted in Cancer GPS? cancer cells often have abnormal DNA methylation patterns — excess methylation (hypermethylation) in some regions, reduced methylation in others. Methylation acts as a kind of ‘fine tuner’, regulating whether genes are switched on or off. In the methylation landscape of cancer cells there is an overall loss of methylation but there’s an increase in regions that regulate the expression of critical genes. This shows up as clusters of methylated cytosine bases.

Rather helpfully, a little while ago in Desperately SEEKing … we talked about epigenetics and included a scheme showing how differences in methylation clusters can identify normal cells and a variety of cancers and how these were analysed in the computer program CancerLocator.

The Trau paper has an even better scheme showing how the patterns of DNA decoration differ between normal and cancer cells and how this ‘methylscape’ (methylation landscape) affects the physical behaviour of DNA.

How epigenetic changes affect DNA. Scheme shows methylation (left: addition of a methyl group to a cytosine base in DNA) in the process of epigenetic reprogramming in cancer cells. This change in the methylation landscape affects the solubility of DNA and its adsorption by gold (from Sina et al. 2018).

Critically, normal and cancer epigenomes differ in stickiness — affinity — for metal surfaces, in particular for gold. In a clever ploy this work incorporated a colour change as indicator. We don’t need to bother with the details — and the result is easy to describe. DNA, extracted from a small blood sample, is added to water containing tiny gold nanoparticles. The colour indicator makes the water pink. If the DNA is from cancer cells the water retains its original colour. If it’s normal DNA from healthy cells the different binding properties turns the water blue.

By this test the Brisbane group have been able to identify DNA from breast, prostate and colorectal cancers as well as from lymphomas.

So effective is this method that it can detect circulating free DNA from tumour cells within 10 minutes of taking a blood sample.

The aim of the game — and the reason why so much effort is being expended — is to detect cancers much earlier than current methods (mammography, etc.) can manage. The idea is that if we can do this not weeks or months but perhaps years earlier, at that stage cancers may be much more susceptible to drug treatments. Trau’s paper notes that their test is sensitive enough to detect very low levels of cancer DNA — not the same thing as early detection but suggestive none the less.

So there are now at least three non-invasive tests for cancer: liquid biopsy, Breath Biopsy and the Queensland group’s Methylscape, and in the context of epigenetics we should also bear in mind the CancerLocator analysis programme.

Matt Trau acknowledges, speaking of Methylscape, that “We certainly don’t know yet whether it’s the holy grail for all cancer diagnostics, but it looks really interesting as an incredibly simple universal marker for cancer …” We know already that liquid biopsies can give useful information about patient response to treatment but it will be a while before we can determine how far back any of these methods can push the detection frontier. In the meantime it would be surprising if these tests were not being applied to age-grouped sets of normal individuals — because one would expect the frequency of cancer indication to be lower in younger people.

From a scientific point of view it would be exciting if a significant proportion of ‘positives’ was detected in, say, 20 to 30 year olds. Such a result would, however, raise some very tricky questions in terms of what, at the moment, should be done with those findings.

Reference

Abu Ali Ibn Sina, Laura G. Carrascosa, Ziyu Liang, Yadveer S. Grewal, Andri Wardiana, Muhammad J. A. Shiddiky, Robert A. Gardiner, Hemamali Samaratunga, Maher K. Gandhi, Rodney J. Scott, Darren Korbie & Matt Trau (2018). Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker. Nature Communications 9, Article number: 4915.

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Born On Wings

 

Alexander Porfiryevich Borodin is a name that will perhaps be familiar only to musical folk of a fairly dedicated kind. Which is a shame because he wrote some wonderful music particularly in his symphonies, in the magical portrait of the steppes of Central Asia and in his opera Prince Igor, albeit not finishing the latter. But Borodin was more than just a gifted composer for he started life as an illegitimate child, qualified as a doctor in Saint Petersburg and became a Professor of Chemistry at the Imperial Medical-Surgical Academy in that city. He carried out some very significant chemical research – he’s even got a reaction named after him – whilst, as a hobby, becoming a sufficiently outstanding composer to be one of The Mighty Handful. Along the way he founded the School of Medicine for Women in Saint Petersburg, the first Russian medical institute for women.

Advanced chemistry

With that background we can be sure that Borodin would have been thrilled to note the recent headlines about the trial of a breathalyser test for cancers. It’s being run by my colleague Rebecca Fitzgerald of the Cancer Research UK Cambridge Centre (and of tea bag fame: see Open Wide for Pasty’s Throat), initially for people suspected to have oesophageal or stomach cancers but in time to be extended to other cancers. What would have excited the chemist in Borodin is that the test collects airborne molecules from the breath and uses the most advanced modern chemistry to analyse them (the details don’t matter but, for the record, the critical method is called Field Asymmetric Ion Mobility Spectroscopy (FAIMS) which distinguishes molecules by how fast they move when driven through a gas by an electric field).

What’s new?

At first pass it may sound fanciful to think of detecting cancer on the breath but perhaps it shouldn’t. After all, we’re familiar with breathalysers that detect alcohol levels and, more generally, we all know that ‘bad breath’ isn’t a good sign. For example, the smell of acetone on the breath can arise from type I diabetes, when the body increases its use of fat due to low insulin levels. My old chemistry teacher was known throughout the school as ‘Fruity’ — the word he used with relish to describe the scent of ketones (acetone is the smallest member of the ketones).

The general point is that molecules released from cells can find their way into the lungs and emerge in the breath and now they can be identifed to find signatures indicative of disease.

The detection of breath-born chemicals can inform diagnosis and treatment of disease. From ebook “Breath Biopsy: The Complete Guide” by Owlstone Medical Ltd.

Pioneering this approach is a company called Owlstone Medical whose Breath Biopsy analytical platform carries out the spectroscopy of airborne molecules (volatile organic compounds). The idea is that someone exhales into a mask and chemicals born on the breath are collected by a cartridge for subsequent analysis. More than 1000 different compounds can be identified by this state-of-the-art technology and for cancer detection these may include substances released by tumour cells and also those emanating from host cells that have been drawn into the tumour microenvironment.

Followers of this blog will know of my enthusiasm for cancer early detection, in particular the liquid biopsy method that permits the isolation of tumour DNA from small blood samples. The breathalyzer system is a different approach to the same problem — and it may be that, in the end, both will have useful roles to play. I should add that my publicizing Owlstone Medical is entirely on account of the apparent potential of their system for cancer screening. Although the company is based in Cambridge, I have no connection with them. I rather wish I had.

If Borodin was here to comment he might wryly observe that in his opera the breaths launched by the enslaved captives when they start to sing ‘Born on wings …’ carried only grief and sorrow but with Breath Biopsy it may be that bad news enwraps good — if it carries a warning of cancers or other diseases sufficiently early that they may be stopped in their tracks.