You might not have thought of it in quite this way but cancer biology is a bit like having kids. It seems you only have to turn your back and things have changed, not so as to be unrecognizable but enough to have you blinking in surprise, shock or horror. In the cancer field it’s true that, especially over the 12 years since human DNA was first completely sequenced, a fair bit of the jaw-dropping has been due to astonishing technical advances. Thus human genomes (i.e. their DNA sequence) can be laid bare in 24 hours – The International Cancer Genome Consortium now has over 10,000 cancer genomes in its database – and the power of the panoply of ’omics methods to probe ever deeper into the mind-boggling complexity of tumours is quite staggering (we risked a quick peep at just how tricky it is to disentangle a picture of the biology from the vast amounts of data in A Word From The Nerds).
These revelations often leave us gasping at the variety and adaptability of nature and how that shows up time and again in the microworld of cancers. Of course, we’re used to the world being ever-changing but we like to think there are some things that are fixed. The Earth still rolled round the Sun even after the aeroplane was invented. When it comes to cancer the simple but fairly firm idea is that cells pick up changes in their genetic material (i.e. mutations in DNA) and if these affect an appropriate set of genes (i.e. encoded proteins) a cell starts misbehaving – multiplying when it shouldn’t or faster than normal. And that’s cancer. Of the twenty-odd thousand genes that make human beings, several hundred have this ability to be trouble-makers – and a handful at any one time (perhaps five to ten) is all it takes. Like any team, there are some high profile players: genes that crop up time and again in mutant form driving all sorts of different tumours. There’s maybe a dozen of these. The rest are bit part players: actors who can steal the show with a cameo role. In others words they’re low frequency cancer drivers, perfectly capable of doing the job but generally keeping a low profile.
All of which is fine: we can hang on to what we thought we knew. Cancers are caused by cumulative mutations – things are just complicated a bit because of the more or less infinite subtlety that the different combinations can cause. So cancer’s really pretty simple.
Oh no it’s not!
However, just once in a while – mercifully, or we’d all go potty – something comes along that has us, if not standing on our heads, at least wondering which way is up. Welcome Iñigo Martincorena, Peter Campbell and pals from The Sanger Institute in Cambridge – a regular source of wide-eyed wonder in genomics.
They’ve just done something that, on the face of it, was very odd. They carried out a thorough sequence analysis of samples of normal human skin, the skin in question being from eyelids. The plan was to try to get a picture of how cancers develop and eyelid skin is a good place to look because it gets a relatively high exposure to sun. Moreover, it’s easier to get hold of than you might think: there’s an age-related condition in which the skin loses its elasticity causing the eyelid to droop – which can be treated by surgery, i.e. cutting out some of the skin.
Fasten your seat belts: here comes the shaker. In 234 eyelid samples (biopsies) from four people the number of mutations was similar to that in many cancers! Yet more amazing, the mutated genes included most of the key ‘drivers’ of one of the major forms of skin cancer.
Putting numbers on it, they found about 140 driver mutations per square centimeter of skin.
The type of DNA damage was characteristic of the effect of ultraviolet light (e.g., changing C to T – i.e. the base cytosine is mutated to thymine) – so at least that wasn’t a surprise.
Groups of mutant cells (clones) in a 1 square centimeter of normal eyelid skin.
The circles represent samples of skin that were sequenced. Their sizes and the representation of nested clones are based on the sequences obtained. The outermost layers of normal skin can therefore be viewed as “effectively a battlefield of hundreds of competing mutant clones in every square centimeter of skin.” (from Martincorena et al. 2015).
As Iñigo & Co put it ‘aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations.’ Notably, there were clones carrying two or three driver mutations – and yet the tissue showed no sign of cancer and functioned quite normally (apart from its wonky elastic).
Close your eyes: time for a re-think
So, there are thousands of mutations in each skin cell with hundreds of evolving clones per square centimeter and the profile of driver mutations varies between individuals. The obvious question, therefore, is ‘why isn’t this tissue cancerous?’ We don’t know but, given that key ‘drivers’ are present, it seems that these cells either have a kind of master ‘off switch’ that suppresses potent driver combinations or they need a further ‘on switch.’ There’s no evidence for either of these, nor is it clear whether other cell types can show this kind of restraint.
And there’s one more troubling point. Many cancer drugs are designed to target driver mutations and thus to kill the carrier cells. But if these mutations can crop up in normal cells, any such ‘cancer specific’ drugs might cause a good deal of what the military term collateral damage.
As ever in science, an exciting new finding raises yet more questions. Answers will be forthcoming at some point. Just don’t blink!
Martincorena, I. et al. (2015). High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886.