G is for Genetic Destiny

What’s your kryptonite? Every superhero has one. That weakness that follows you through your life, returning, recurring, a constant threat that lurks in the shadows, ever present; never quite vanquished. Breast cancer is my kryptonite. My mother was diagnosed when I was 4, she died when I was 9 and I was diagnosed when I was 32. So from being a little girl with a poorly mum, to a teenager growing up without her, to a young(ish) woman in treatment, breast cancer has – to one degree or another – shaped my whole life and made my experience different from the ‘norm’. Two years ago, thanks to the genetics team at Great Ormond Street Hospital and around 40 years of scientific research, I finally found out why…

Too small to see; too enormous to contemplate

Breast cancer has been known to run in families since the 1940s, but it was not until 1990 – the same year that we lost my mum – that a crucial discovery was made that would eventually explain her breast cancer, and revolutionise cancer research. On Oct 17th, 1990, Mary Claire King addressed the annual convention of the American Society of Human Genetics, and announced that after 17 years of painstaking research her team had identified irrefutable evidence that there definitely was a gene responsible for inherited predisposition to early onset breast cancer, and that it resided somewhere on chromosome 17. Thrilling, ground-breaking, and life-changing – this was Alan Turing cracking the Enigma Code; the Higgs-Boson breakthrough of breast cancer genetics. It was also the equivalent of confirming the existence of a known terrorist, somewhere in the region of Greater London. To get anywhere close to understanding and foiling the plot would require the specific address.

What followed was an international race to isolate the gene, and “zero in on a piece of DNA too small to see, for a prize too enormous to contemplate”¹. Over the next four years – in a world of paper and pens, long before the era of mobile, email or data analytics – scientists around the world made incremental breakthroughs that closed in further and further on the elusive BReast CAncer gene, until in 1994 Professor Mark Skolznik and his team at the University of Utah were able to call it – they had isolated BRCA1. They had found the proverbial needle in the haystack – at chromosome 17, region 2, band 1, between base pair 41,196,312 and 41,277,500 (for context, there are an estimated 3.2 BILLION base pairs in the human genome). Why this has not yet been the subject of a thrilling feel-good film starring Tom Hanks, or at least a Sunday night television drama, is anybody’s guess (and Aaron Sorkin, if you’re reading, I reckon this is right up your street).

Unlucky Number 13

But this was only the start of the riddle. Although scientists had isolated BRCA1, they had no idea what it did, or why it was linked to hereditary breast cancer – they knew where the terrorist was hiding out but they had no notion of the plan. And there were families in the gene studies with multiple cases of male and female breast cancer which couldn’t be explained by BRCA1, raising the tantalising possibility of another breast cancer gene. This time the Brits had it, and in 1995 Professor Sir Mike Stratton and Dr Richard Wooster at the Institute of Cancer Research identified errors in a gene on chromosome 13 in families with breast cancer which were not present in the DNA from healthy women. They had discovered BRCA2. Since then, scientists have isolated hundreds of different mutations in both of these genes, many of which have been found to be common to specific population groups, and can therefore be traced back to a single, common ancestor – for example, in Iceland a single mutation accounts for almost all families with breast or ovarian cancer. Mutations in BRCA1 and BRCA2 have been the cause of breast and ovarian cancer in families for hundreds of years, but it wasn’t until their discovery just 20 years ago that we started to understand why.

The BRCA2 Cycle Path, from Addenbrookes Hospital to Great Shelford, by Keith Edkins. Image licensed under Creative Commons Attribution-ShareAlike 2.0 license. 10,257 stripes represent the four nucleotides of the BRCA2 gene.

Heads or Tails?

Had I known then what I know now, I would have spent less time writing “Emma 4 Leo 4Ever” in the back of my (impeccably organised) binder, and more paying attention to GCSE Biology. Without getting deep into the mechanics of what the BRCA genes do and how they work, it will suffice to say that BRCA genes are present in everyone, in cells throughout the body. It is mutations in the genes – not the genes themselves – that increase the risk of cancer, and every child of a parent with a BRCA mutation has a 50% chance of inheriting it. Heads you win; tails you lose.

The BRCA genes have been the subject of extensive research which has opened up the possibility of targeted therapies, and preventative treatments, but there are numerous questions still to be answered – and more genes to be discovered.

Things we know:

Around 1 in 800 people carry a BRCA defect, but this varies by population²
Inherited defects account for 5-10% of breast cancers (around 80,000 to 160,000 cases globally per year); BRCA defects are a portion of these³
Depending on the type (1 or 2), a BRCA defect means a woman has a 45-90% risk of developing breast cancer in her lifetime (compared to the UK population risk of 12.5%), and a 10-60% risk of developing ovarian cancer (compared to the UK population risk of 2%) ⁴
Cancer in younger women is more likely to be caused by a BRCA defect and can be harder to treat
BRCA2 is also linked to male breast cancer, prostate, pancreatic and skin cancer. A man with the BRCA defect has a 20-25% risk of developing prostate cancer, and 7% risk of developing breast cancer.

Things yet to be discovered:

What factors trigger cancer in the carrier of a BRCA defect, and why some people with a BRCA defect never develop cancer
Why BRCA defects don’t cause other types of cancer
All the other genes which cause breast cancer (though others have been identified, tests are not necessarily available)

The Angelina Effect

Of course, you probably already knew at least a little of all of that, because unless you’ve been living in a cave you’ve heard of Angelina Jolie – actress, United Nations Goodwill Ambassador, and one half of the global powerhouse of superstardom that is ‘Brangelina’ – and Angelina Jolie is the most famous carrier of a BRCA defect in the universe. Yes, you heard me correctly, Angelina Jolie and I have something in common, and it’s that we are both genetically DEFECTIVE (and, I will concede, that is probably where our similarities end). Angelina’s mother suffered from ovarian cancer, and Angelina discovered that she had inherited a BRCA1 defect which resulted in her announcement that she had undergone a preventative mastectomy and reconstruction to reduce her risks of developing breast cancer. It was the New York Times article that launched a thousand magazine headlines – and at least a couple of soap opera storylines – about inherited breast cancer and preventative mastectomies. Sharing with Angelina, as I do, a very personal loss and a very defective gene, I respect and applaud her decision to use her celebrity to explode awareness of the issue, and her courage in making an intensely private matter public. Unfortunately the media, which appears to be in increasing danger of assuming that we are all too stupid and time-pressed to digest anything longer and more complicated than 140 characters, have not always echoed her careful and considered approach, risking a popular perception that BRCA is straightforward; a ‘no-brainer’ that can be easily managed away through a prophylactic boob job.

What Angelina Jolie must know as well as I do, and anyone else in our particular boat, is that there is nothing about BRCA that is simple, casual, or indeed red-carpet-ready. Somewhere at the heart of every BRCA defect is a sad story. At its very best it means young women having to take deeply unenviable and drastic steps to protect their health – steps that are incredibly easy to speculate on hypothetically, but much harder to face in real life. At its worst it means generations of the same family – mothers, sisters and daughters, and fathers, brothers and sons – blighted by the same disease. Cancer is the great equaliser, and that is the brutal reality of the BRCA defect whether you’re Hollywood Royalty or a lass from Yorkshire.

The two most important days in your life are the day you are born and the day you find out why – Mark Twain

Finding out what your DNA is made of – who you are at the most fundamental level – is a surreal experience. It is your very own “(Luke), I am your Father” moment, and, whilst you don’t necessarily find yourself screaming “NOOOOOOOOOOOOO” in your best impression of an anguished Luke Skywalker, nothing can really prepare you for the complex cauldron of emotions as a geneticist tells you that they have read the entire ‘War and Peace’ of your DNA, and happened upon a tiny but crucial mistake, deep within Chapter 13, that changes the course of the whole book.

For me it was simultaneously humbling, upsetting and comforting. Humbling, because this is the culmination of decades of scientific endeavour and human progress. I am here, in this consulting room, finding out the very essence of who I am and how I work because generations of people have tenaciously kept asking ‘why?’ and ‘how?’, and I am privileged to be the recipient of this most remarkable knowledge. Upsetting, because here is the confirmation that part of me is broken and can never be fixed. My body is doing exactly what it knows how to do, and it cannot protect me from the harm it is inflicting upon itself – it is the miracle of nature at her most capricious. Other members of my family will now also have to face this prospect, and decide how much they want to know. And the person with whom I share this most fundamental feature is the one person I cannot share the news or experience with. That which unites me and my mother more than anything else – this shared inheritance that has dictated the course of both our lives – is that which also divided us, and I am full of sorrow about all of it, on all of our behalves. Mainly, though, I am comforted. Comforted because here, in black and white scientific fact, is a logical reason why the things that have happened have happened. From the moment I made my entrance into the world on a festive December day in 1980 – and actually 9 months prior to that if we’re splitting scientific hairs – breast cancer was a highly likely part of my destiny, just as it was for my mum when her genetic code was written way back in 1953. There is nothing I could have done differently; none of it is my fault. ‘Why?’, and ‘Why me?’ are now questions that I can answer with absolute certainty, and I draw great solace from that.

DNA neither cares nor knows. DNA just is. And we dance to its music – Richard Dawkins

At the Roulette Table

However, far from providing all the answers, a BRCA diagnosis opens another Pandora’s box of problematic questions to be faced. So you know you have a vastly increased risk of developing breast and ovarian cancer in your lifetime, but you don’t know when, or indeed IF it will occur. What are you going to do about it? How do you fancy your odds in the great casino of medical probabilities? You have the enormous advantage of knowing your enemy, and how it might behave, but the intelligence is in no way complete, and no war is won without collateral damage. At the extremes the strategies you now have available to you include removing your healthy breasts to drastically reduce but not eradicate your risk, with all the potential complications and consequences that could imply; removing your ovaries for the not-so-bargain price of an early menopause and restricted fertility; and rolling the dice on when exactly you should do all of this, because the odds are telling that you probably have some time, but cancer could stage an ambush at any moment. The ‘simple’ question of if or when to start a family is no longer straightforward, not least because the hormones that surge during pregnancy are now known to play a fundamental role in triggering BRCA related cancer⁵. More profound than this, without embryo screening there is a 50/50 chance you will pass this fate onto your children, and – if you don’t take all the most drastic steps to protect against it and the worst does happen – you could be sentencing yourself and your family to a life punctuated by cancer.

If the picture I paint appears stark, that’s because it is. In the choice between cancer and ‘almost anything else’, ‘almost anything else’ is almost certainly going to be the preferred option, but that doesn’t make it easy or without consequences. The ‘right’ course of action can appear obvious in theory at the level of a newspaper headline, but the reality is altogether more nuanced. Every choice is a gamble, and every play comes at a price. There are no ‘no-brainers’ here – just a series of options, each as undesirable as the next, and whatever you decide it will likely be with a heart that is heavy from the weight of future fears, forfeited hopes and past loss. One way or another the House always wins.

At the Frontier

In many respects carriers of the BRCA defect are at the frontier of the upcoming personal genetic revolution – they are facing the types of dilemmas and decisions that will eventually become commonplace as we are able to routinely understand if we are at increased risk of any number of inherited conditions, from Alzheimer’s to heart disease. And at any Frontier or Wild West town there are profiteers moulding an unregulated market to their own advantage. In the US the BRCA1 and BRCA2 genes were controversially patented on discovery by Myriad Genetics, which established them as the sole provider of the genetic test at a prohibitive cost of up to $4000, and restricted research by other scientists. The patents were finally overturned after 18 years in a landmark decision by the US Supreme Court in 2013 which legally established DNA segments as products of nature which are not patent eligible. The same patents were overturned by the High Court of Australia just 8 weeks ago. Myriad also held European patents which covered the UK. Fortunately our bold British bulldog NHS turned a blind eye to the inconsequential issue of international patents, and in true frontier spirit developed its own simpler and cheaper tests using publicly available data. That is not to say, however, that the UK has got the protection of patients all wrapped up. The results of a genetic test can also restrict access or vastly increase the cost of health, life insurance and other financial products. The UK Government have agreed a temporary Moratorium on insurance companies asking people for the results of genetic tests for cancer, which expires in 2019. There is no guarantee it will be extended. As more genes are discovered, and accessibility to genetic testing is increased, there is a very real possibility that corporate ‘risk’ will come to outweigh patient rights, and ensuring access to insurance or a mortgage could become the deciding factor in whether or not you take a test that could protect your future health.

The deeper I delve into the BRCA conundrum, and the more I learn about the thrilling medical advances that are being made every day, the more convinced I become that, as a society, and as individuals, we’re nowhere near ready to answer the pressing questions that science and technology are hurtling our way. Perhaps one of the most unsettling dilemmas – the one which I cannot help but take rather personally – is that of embryo selection. 2009 saw the birth of the first ‘BRCA1-free’ baby after pre-implantation genetic diagnosis – a form of embryo screening available to BRCA defect carriers embarking on IVF. I consider myself fortunate to live in a society that has invested in a making this medical miracle available as an option, and respects the freedom of a parent to make that choice. Beyond that I’m not sure what I think. What I am completely sure of is that the defect in my BRCA gene is part of the unique code that makes me ‘Emma’ – green eyes, broad shoulders, and appalling hand-eye coordination. Obviously, in a different, make-believe fantasy world where you get to choose, I would choose not to have a genetic defect that resulted in me developing breast cancer. But in this real world, where s**t does happen, my BRCA defect is an intrinsic and non-negotiable part of the unique package that is ‘me’. And – I don’t mind telling you – I’m pretty bloody delighted with the rest of the package thanks very much, so I’d rather not dwell on the possibility that I might have been discarded at conception because I was ‘defective’.

Grappling with these existential questions takes me back to Marty McFly in Back To The Future – the ultimate film on destiny (and density) – helplessly watching his hand vanish before his eyes as he vainly attempts to strum the chords to ‘Earth Angel’ at the Enchantment Under the Sea Dance. Marty is being written out of history thanks to his inadvertently messing around with the space-time continuum. I have always maintained that there were numerous benefits to being a child of the ‘80s – Michael J Fox films being just one of them – and I can now add to that list that my parents did not have the option to de-select me out of existence. Let’s imagine for a moment that they did have that option and they chose the other embryo. Let’s call her ‘Emily’. Perfect, blue-eyed, ball-catching, BRCA-negative ‘Emily’. I hate ‘Emily’. She is a cuckoo in my nest and I don’t think she’s all she’s cracked up to be. So she might never have developed cancer. Good for her. But she might also have been a prig who couldn’t appreciate the musical genius of Abba, and never perfected a dramatic recitation of the tragic tale of Tony and Lola at the ‘Copacabana’ – so let’s all just take a look at them apples and consider how much we like them. To add insult to grievous injury, had ‘Emily’ been the chosen one I would never even have had the opportunity to be outraged on my own behalf, which is a hypothetical course of events I am quite outraged about. Honestly, it’s enough to drive one to drink – and Barry Manilow’s Greatest Hits.

But it is the same with any life. Imagine one selected day struck out of it, and think how different its course would have been. Pause you who read this, and think for a moment of the long chain of iron or gold, of thorns or flowers, that would never have bound you, but for the formation of the first link on one memorable day. – Charles Dickens, Great Expectations

Breast cancer is my kryptonite, and my DNA is the reason why. Fortunately I was well trained to face the carnage wrought by this enemy within. When I was growing up there was a poem on our hallway wall: ‘Children Learn What They Live’ by Dorothy Law Nolte – “If children live with criticism they learn to condemn, if children live with praise they learn appreciation”, and so on. What it didn’t say, that it really should have, is that if a child lives with heroic strength in the face of extreme adversity, they will learn a little about how to face some of the harder challenges in life. Despite breast cancer doing its worst to our family, my childhood was packed full of laughter, music and joy, and unstoppable activity, education and adventure. Even the toughest challenges – challenges that I am only just now beginning to start to appreciate – were faced with a simple calm, quiet strength and steely determination. My mum and dad showed me what courage and fortitude look like every single day that they got up and got on and made my childhood magical. That is the inheritance that really counts, and it has been priceless.

For nature, heartless, witless nature

Will neither care nor know

What stranger’s feet may find the meadow

And trespass there and go,

Nor ask amid the dews of morning

If they are mine or no.

– A. E. Housman, Last Poems: XL