Family Tree of Breast Cancer

Minding my language

There may be the odd soul out there who has now read Betrayed by Nature and spotted that, just once in while, there’s some very unscientific language. The select band of blog followers (I think of them as The Few) will have noted the same thing (in ‘Touching base with our rellos’, for example). The odd ‘astonishing’ slips out. An occasional ‘incredible’ creeps in – we’ve even been ‘stunned’. “What on earth is he on about?” you might wonder. Scientists aren’t supposed to talk like that. For them it’s measured tones, words weighed with care and, of course, they do sitting on spiky fences with such aplomb you might conclude they’re a bit on the kinky side.

It’s a fair cop

It’s all true. But here’s my defence. Of late, when you might think I’ve been a shade ott, it’s almost always because I’ve been talking about sequencing DNA. Here the events of the last few years have been truly breathtaking. In all respects, I would maintain, they rank among the most awe-inspiring in the history of science. There are two reasons for this belief so let me share them with you, prompted by yet another absolutely remarkable piece of work on cancer that has just been published.

Two astonishing things

First is the technology. Today’s machines can carry out 100s of millions of separate sequencing reactions at the same time (just say that slowly). In the jargon it’s ‘massively parallel sequencing’. How they work matters not here but the ingenuity and engineering that make it possible to find the order of bases in DNA at such speeds is simply mind-boggling.

Second is the outcome. The speed of these gadgets means that the entire DNA sequence of an individual can be obtained in a day or so and that tumours are now being sequenced on an industrial scale. That’s being done to obtain a picture of the sets of mutations that define sub-sets of the major cancers.

The Family Tree of One Individual Breast Tumour

You can’t have too much of a good thing

But these advances mean you can do something else: sequence the same tumour again and again – hundreds of times. Why would you want to do that? The answer is that tumours are a real mixture – a gemisch of groups of cells (called ‘clones’), each descended from a single common ancestor so that the cells in a clone are genetically identical. So, if you really want to know what you’ve got, you need to be able to detect individual clones and the only way to do that is to sequence over and over again until you can get reliable data for the rarer DNA codes that come from smaller clones. That’s just been done for one individual breast tumour and the result is an evolutionary tree showing how the cancer had developed from the fertilized egg to the point it was diagnosed.

The major clones that made up the tumour when it was diagnosed (B, C and D) all descended from a predecessor (A), the most-recent common ancestor. Tens of thousands of mutations went into making A. Thousands more accumulated to form B, C and D. The arrows extending from B, C and D represent the emergence of further clones in what is a continuing, dynamic process. Their record is written in their genomes – a book of progress reports.

One more pretty remarkable thing

In the UK and the USA about 12% of women will be diagnosed with breast cancer. In 2008 world-wide 458,503 women died from the disease and we still have no treatment that is specific in targetting only the tumour cells. It is, therefore, really staggering that improvements in surgery, radiotherapy and drugs in the last 60 years has seen the 5-year survival rate go from 40% to over 90% for white American women and to about 80% in the UK.

Despite this progress, the ideal for every cancer would be to use the family tree to identify the key driving mutations from the tens of thousands in the major clones and then use cocktails of specific drugs to zonk them. At the moment we are a long way from having such an armoury but the current rate of progress in defining tumours at the molecular level, driven by the fabulous technology of sequencing, means that at long last we can proceed on a rational basis, rather than by the time-honoured method of trial and error.

Reference

Nik-Zainal et al., The Life History of 21 Breast Cancers, Cell (2012), doi:10.1016/j.cell.2012.04.023

http://libsta28.lib.cam.ac.uk:2057/science/article/pii/S0092867412005272

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