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Cancer, genomes, evolution and personalised medicine – it’s complicated

7 Mar, 2012

Published today is a fascinating study taking the already complicated story of cancer to a whole new level. It raises some uncomfortable facts, but it does once again demonstrate the power of whole genome sequencing and how this technology is accelerating our understanding of complex disease.

I suggest you read Henry Scowcroft’s excellent write-up on the Cancer Research UK Science Blog for the full story. But the bottom line is: cancer genes differ even within parts of the same tumour in the same patient.

The oft-repeated dogma about cancer is that it comes from mutations causing one cell to go rogue and divide out of control. The implication of this is that each cell is the same as the cancer spreads.

But this isn’t the case. Researchers from the London Research Institute and the UCL Cancer Institute  found that kidney cancer genes can actually differ in different parts of the same tumour. Moreover, different regions of the tumour can show different faults in the same genes.

This has huge implications, not least that sampling just one part of a tumour may not be as representative of a patient’s cancer as we’d like to think (and raising the uncomfortable prospect of needing multiple biopsies from a patient). 

The Wellcome Trust Sanger Institute played a key role in the study, helping to confirm the findings by repeating the experiments using samples from a second patient. From a genomics point of view, it’s fascinating. For one thing, it’s the first ever genome-wide analysis of the variation between different genetic regions of the same tumour.

“We’ve known for some time that tumours are a ‘patchwork’ of faults, but this is the first time we’ve been able to use cutting-edge genome sequencing technology to map out the genetic landscape of a tumour in such exquisite detail.

This has revealed an extraordinary amount of diversity, with more differences between biopsies from the same tumour at the genetic level than there are similarities.”

– Professor Charles Swanton, London Research Institute

It also teaches us much about the evolutionary mechanisms behind cancer. The researchers liken a cancer’s development to a Darwinian tree of life. There are some common mutations in the ‘trunk’ of the tree, but things can be very different from branch to branch – and the type of tree mapped in different cancers’ evolution may be very different. This makes treatment difficult as really what you want to do is target the common mutations in the trunk. But if some cancers have smaller trunks and more branches, you’ve got a much more difficult target to hit.

On the positive side, this may help us understand how cancers build up drug resistance so quickly. Professor Charles Swanton, who led the study, says it explains why surgery to remove a primary kidney tumour can improve a patient’s chance of survival – “[it decreases] the likelihood that resistant cells will be present that could go on to re-grow the tumour after treatment”.

On the more worrying side, it means we have to be careful about what drugs we use. If we hit the branches rather than the trunk, there’s the risk of not quite finishing the job and leaving a few drug-resistant cells that could grow the tumour all over again. I like Ed Yong‘s analogy: “A tumour is like the mythical hydra. If you cut off a head, more will grow back; you need to kill the entire body”.

This has implications for personalised medicine and the clinical use of whole-genome sequencing. Much as has been said about the potential for tailoring treatments to individuals based on their genetic profile. But this is a lot more difficult if the genetic profile of the cancer itself differs within one patient and we’re running the risk of drug resistance.

“The idea of personalised medicine is to tailor treatments to suit individual patients. This study in kidney cancer has shown significant molecular changes between different parts of the same tumour.

We have also seen differences between primary kidney tumours and cancer cells that have spread to other organs. This may be relevant to how we treat kidney cancer with drugs because the molecular changes that drive the growth of the cancer once it has spread may be different from those that drive the growth of the primary tumour.”

– Dr James Larkin, Royal Marsden Hospital

As the researchers said in a press briefing, we need to know much more about individual tumours before we can think about whole-genome sequencing for routine clinical use. It often seems like the main barrier to this is the cost of whole-genome sequencing, but as Swanton pointed out, this isn’t the issue. It’s the processing the results, analysing them, understanding they mean, and whether they can infer a treatment. Swanton’s team are now looking to analyse over 200 different tumours to try to map how each one develops (read the last few paragraphs of Ed Yong’s post to see just how painstaking their methods were, then multiply that by 200).

The picture’s got a little murkier, but we’ve got a better handle on how big might be.


  • Gerlinger, M., Rowan, A., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C., Nohadani, M., Eklund, A., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P., & Swanton, C. (2012). Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing New England Journal of Medicine, 366 (10), 883-892 DOI: 10.1056/NEJMoa1113205
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