by Kirk, Edwin;
Do these new changes in the DNA matter? It depends on exactly where the mistake happens. It can matter a great deal, as we shall discover. But mostly the changes happen in places where it doesn’t matter much: in between the genes, or in other places where it doesn’t make a difference if you change a C to a T or an A to a G.
What about your body’s allotted ten quadrillion cell divisions? How accurately is the DNA copied? Well, a recent study suggests that, typically, there is one new mistake per cell division. Yes, that’s right — almost every time a cell divides, something goes wrong, and the genome is imperfectly copied. Your genome is decaying, every minute of every day. In a very real sense, you don’t have ‘a’ genome — you have trillions of slightly different versions of the genome you started with. Almost no two cells share the exact same genetic make-up as each other.
If you have three billion bases of DNA, and there are ten quadrillion opportunities for it to be incorrectly copied, it follows that practically every single simple genetic change that is possible must happen many, many times over in a person’s lifetime. Plenty of chances for the brake genes to be damaged and to stop working, or for accelerator genes to be jammed in the ‘on’ position. Or for completely new accelerator genes to be created, as when the Philadelphia chromosome is formed.
You might ask how any of us are alive; how is it possible to survive from conception to birth without having cancer, let alone through childhood and into adult life?
It turns out that there are a couple of different answers to that. Firstly, and most importantly, the transformation from healthy cell to cancer cell is not something that happens overnight, or (usually) as the result of a single genetic mistake. There are backup systems in place, so that, for the most part, a single error isn’t enough to cause cancer — there need to be more piled on top of the first one, and of course they all have to happen in the very same cell. It’s a bit tricky working out exactly how many mistakes it takes, because one of the features of cancer cells is that their DNA copying often gets sloppy, leading to mistakes being made. Some of these aren’t part of why a cell is cancerous, but are a consequence of the chaos that goes along with being a cancer cell. This means that as well as ‘driver’ mutations, there are also ‘passengers’4 — not the cause of the problem, but along for the ride — and, when we study the DNA of cancer cells, it isn’t always obvious who’s doing what.
[4 In this case, a ‘driver’ can be either a faulty brake or an overactive accelerator. It’s anything that makes the cells grow faster.]
Thanks to our ability to sequence the whole genome of a tumour and compare it with healthy tissue, we are building up a picture of what it takes to go from being a well-behaved, functional cell to being a menace to society. It turns out that it’s probably not a very large number of mistakes — often as few as six or seven, and for some types of cancer it can be even fewer, maybe just one or two. But remember that they have to be exactly the right (or wrong) combination of mistakes. Our bodies are full of almost-cancers that will sit there and never bother us.
How frightening is the problem? Well, if you are of a nervous disposition, you may want to skip this next bit.
They probably didn’t think of it in quite this way, but, in 2015, a group of scientists from the United Kingdom set about working out exactly how scary the problem is. Four people who were having operations to tighten up sagging upper eyelids donated the excess skin for research. The skin samples looked completely normal under the microscope. The researchers in question took the leftover bits of skin, punched out 234 tiny biopsies, and read the genetic sequence in each of them. They looked only at a set of 74 genes that were known to be involved in the development of cancer, and within that they looked for changes in the genes that they could reasonably identify as potential drivers for cancer.
I don’t know what they expected to find, but what they actually found was … horrifying. Here’s an image from the paper:5
[5 From DOI: 10.1126/science.aaa6806. Reprinted with permission from AAAS.]
This picture represents one square centimetre of skin. Every circle is a region filled by cells that have a potential cancer-driver mutation. Each circle would have started as one cell that multiplied and expanded until its daughter cells filled the space. Where there are overlaps, there are cells that have more than one driver mutation. Five key genes or sets of genes get their own colours, and the other 67 genes are represented by the unfilled circles.
Here’s some consolation if that’s freaking you out a bit (it certainly gave me the willies when I first read the paper). This was sun exposed skin, and the changes were mainly the sort of changes caused by ultraviolet radiation.6 Also, the volunteers were aged 55–73. You wouldn’t find anything like this picture in, say, a piece of muscle sampled from a 20-year-old. On the other hand, these were all Brits. You call that sun exposure?
[6 Nowadays, I don’t even turn on the lights without putting on sunscreen first. You can’t be too careful.]
So why aren’t we all dead already? Firstly, you do need that series of unlucky breaks to happen to the same cell. Secondly, your immune system is pretty good at mopping up cancer cells — before any cancer can establish itself and get growing, it has to evade the cellular police. For this reason, people with immune deficiencies are at increased risk of getting cancer.
There’s another group of people who are at increased risk of getting cancer. Some people are unlucky enough to inherit a faulty brake or accelerator gene from one of their parents. If the change is there in every single cell from the word go, potential cancers have a head start. And so we see bowel cancer families, breast and ovarian cancer families, and so on. In families like this, cancers tend to be diagnosed at much younger ages than usual — because the cancer cells have been brewing since much earlier. So when we see a family in which there are multiple people affected by cancers that we know can be associated with a particular gene (like breast and ovarian cancer are), and many of them are being diagnosed at a young age — we suspect there may be one of these conditions in the family.
There are a surprising number of different conditions like this, but most of them are very rare. By far the most common involve a high risk of (mainly) bowel cancer and a high risk of (mainly) breast or ovarian cancer. It’s not always as easy as you might think to spot families with such a condition. Cancer is common, and you can get what looks like a familial cancer syndrome just by bad luck. On the other hand, it’s an increased risk, not a certainty, and there are many people who inherit one of these faulty genes but get away with it, living their whole lives unaffected by cancer. On top of that, men who inherit a mutation in one of the breast cancer genes, BRCA1 or BRCA2, are much less likely than the women to get cancer. They can get breast cancer — far more frequently than the general population, but it’s still uncommon. They have an increased risk of some other types of cancer, too, but the pattern is much less distinctive. All of this means that, sometimes, the family trees can be confusing and hard to sort out.
This was also one of the challenges faced by the people who were trying to find these genes in the first place. Nowadays, it’s possible to make a link between a genetic condition and a specific gene by studying a remarkably small number of affected people. This is because we have access to the sequence of the human genome, and because of the power of the new genetic sequencing technologies. For example, my recent PhD student Emma Palmer is working on the epileptic encephalopathies, a group of severe neurological conditions that affect small babies. In the course of her PhD studies, she played a major role in discovering that faults in no fewer than four different genes can cause epileptic encephalopathy. Terrific researcher though Emma is, this would have been an inconceivable feat for one PhD student until the last few years.
In the late 1980s and through to the mid-1990s, when BRCA1 and BRCA2 were found, it was a long, hard slog making such a discovery. BRCA1 and BRCA2 are brake genes, and mutat
ions in the genes lift the cells’ feet (as it were) off the brake a little. It had been recognised for decades that some families have an inherited form of breast and ovarian cancer, with younger age at diagnosis on average than is usual for affected people in the general population. Over a number of years, researchers looked for genetic markers that could lead them to the genes. Think of the fly maps from the previous chapter, but, instead of finding that visible features like yellow body and white eyes were linked, the researchers were trying to find variable stretches of DNA that were connected to the occurrence of cancer. The closer they got to their targets, the tighter that linkage would be.
The process involved hundreds of researchers and many, many family members who volunteered as research subjects. In 1990, a group of researchers led by Mary-Claire King at the University of California, Berkeley announced that they had narrowed down the location of BRCA1 to chromosome 17. Gradually, her group and others whittled away at the chromosome. In May 1994, a group from the University of Utah, in collaboration with a group from Cambridge University in the UK, published a detailed map of the region, which by then contained only a little over 20 genes, one of which must be BRCA1. By October 1994, the race to find the gene was won … but along with the announcement, and publication of the sequence of the gene, by Mark Skolnick and colleagues from the University of Utah, came a shock for those in the field. A company called Myriad Genetics, formed by Skolnick’s group, had applied for a patent on the gene. This was one of a series of patents that essentially tied up commercial testing for BRCA1. And then they did it again. In a similar international effort, the location of BRCA2 had been narrowed down to chromosome 13. In December 1995, another British-led group, headed by Michael Stratton, published the sequence of BRCA2. But the day before the paper was published, Myriad announced that it, too, had found the gene, and had filed for a patent.
To most people in the field, the idea of patenting a gene seemed, and seems, absurd. Myriad didn’t invent either gene, after all — they discovered it. Moreover, Myriad’s discoveries would not have been possible without the work done to map the genes by many other, publicly funded groups, and all of that work rested on patients who volunteered to take part in research. It seemed deeply wrong to most of us that a company could profit from this. But profit they did, and for a long time.
This played out differently in different parts of the world. In the US, Myriad held a stranglehold on diagnostic testing for BRCA1 and BRCA2 for nearly 20 years, until finally the US Supreme Court struck down their key patents, which previously had been repeatedly upheld by lower courts. In Australia, a company called GTG had a patent on all of the genome that did not code for genes — i.e. most of it. Spoiler alert: GTG didn’t invent that either — but they had still been granted a patent for it, and they had argued that Myriad had infringed this patent. The end result was a deal that left GTG holding the BRCA patents in Australia. This was highly controversial and never really enforced, but it was a big relief to the field when the High Court of Australia also struck down the patents, in 2015.
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It has been said that women have double the number of relatives that men do. When we take a family history from a woman, we generally learn twice as much about the family as we would if we had spoken to her brother instead. Sometimes, this really matters. When I saw the boy who wasn’t short, I took a family history from his mother, because this is something we always do. She knew that her first cousin, her uncle’s daughter, had recently been diagnosed with breast cancer at the age of 50. She also knew about two others in the family who had died of breast cancer at a young age, and another who had died of ovarian cancer. She didn’t know that breast and ovarian cancer could be inherited, so it didn’t occur to her to seek advice, and, in any case, we usually start by testing someone who is affected by cancer. Her cousin’s doctors could have put the pieces together — if her cousin’s father had known and passed on the information.
When I learned of the family history, I arranged for the cousin to be seen by a cancer genetics service. They tested her, and found that she carried a mutation in BRCA1. Later, the woman I had seen also decided to be tested, and found that she, too, had inherited the faulty copy of the gene. In one sense, of course, this was bad news for her — far better not to learn that you are at high risk of cancer. But this gave her options, which included having more extensive screening than she would otherwise have had, with a chance of detecting cancers early, meaning a better chance of cure. It also gave her the option of having risk-reducing surgery — removal of her ovaries and breasts before cancer had a chance to develop. A tough choice, but one that we know can reduce the chance that BRCA1 mutation carriers will die from cancer. Several other women in the family had the opportunity to be tested as well. It’s likely that sooner or later, someone in the family will have their life saved by this information.
Although I’m a doctor, Angelina Jolie has saved far more lives than I ever have or could hope to. When she told the story of learning that she, too, carried a BRCA1 mutation, and of her choice to have surgery, our cancer genetics services were swamped with people who had considered their family history in a new light and sought testing. We called this the Jolie effect. As a result, our labs were flooded with samples, many of which tested positive. The rate of people having risk-reducing surgery, as Jolie had done, doubled in Australia and in the US, and probably in many other countries. There are people who are alive today only because of Jolie’s decision to speak out.
The risks for people with BRCA1 and BRCA2 mutations are greatly increased compared with the general population, but there are no certainties. Some carriers live their lives unaffected by cancer, while others with the same genetic make-up die young. This means that making a choice to have surgery represents a decision in the face of uncertainty.
Offering people choices with uncertain outcomes is standard operating practice in genetics, as we shall see.
4
Uncertainty
Fate shuffles the cards and we play.
ARTHUR SCHOPENHAUER
Fate is not an eagle, it creeps like a rat.
ELIZABETH BOWEN
Jason couldn’t remember a time when things had been okay at home. When he was a small boy, perhaps they had been. But then his father started to have violent mood swings; he would fly into a rage over nothing at all. There was never any violence, but Jason’s parents fought constantly, for years. Eventually, when Jason was 12, his mother packed up their things and left, taking him and his sister to live in a different state. Jason never saw his father again.
Years later, thinking back on that time, Jason would wonder if perhaps his father had already been showing the first signs of the sickness that would, eventually, claim his life.
When I met Jason, he was in his early 30s. He and his partner, Lauren, had been living together for two years. They were thinking of marriage, of having children, of a future spent together. But first, Jason wanted to find out if he had a future at all.
Jason showed me a letter he had received eight years earlier. Addressed ‘to whom it may concern’, the letter said that Jason’s father had been diagnosed with Huntington disease, that this meant that his relatives were at risk of also developing the condition, and that the recipient might want to consider speaking to a clinical genetics unit about this information.
Huntington disease1 is not rare by the standards of genetic conditions — it affects about 1 in 10,000 people. It’s a cruel condition, with a characteristic trio of effects: a movement disorder, psychiatric problems, and a decline of mental function. There is a great deal of variation in the way that HD symptoms start and progress, but a typical story is of someone who had previously been well reaching his or her early 40s and starting to show signs of being affected. At first, these are subtle, easy to dismiss as by-products of normal ageing and entry to the middle years of life, rather than something more sinister: clumsiness, apathy, anxiet
y. Other people may start to notice that the affected person is having involuntary movements — twitching of the limbs and face. Depression may set in; balance and the ability to do complex physical tasks are lost. Over time, the brain’s decline becomes worse and worse; eventually affected people lose the ability to care for themselves, to walk, to speak, and to swallow. All of this takes years; most survive a decade or even two after the first symptoms begin. It is a process of slow neurological demolition.
[1 As we shall see in chapter 7, it’s not at all unusual that George Huntington’s 1872 description of the condition that has borne his name ever since was not the first such description … or the second, or the third. Others had beaten him to it with publications in 1832, 1841 (and 1842), 1846, 1860, and 1863. Five others could have had their names attached to the condition, but didn’t. Three of them published their descriptions before Huntington was even born!]
From the earliest descriptions in the first half of the 19th century, the familial nature of the condition was recognised. HD is inherited in a dominant fashion: if you’re affected then each of your children have a 1 in 2 chance of inheriting the faulty gene and being at risk. There’s something special about the fault in the gene: HD is one of a class of conditions known as triplet repeat disorders. You’ll remember the genetic code, made up of groups of three base pairs of DNA. In Huntington disease, the problem lies with a repetitive stretch of DNA: CAG CAG CAG CAG CAG … This codes for the amino acid glutamine, so that in one stretch near the beginning of the protein you have glutamine-glutamine-glutamine-glutamine-glutamine … and so on. Most of us have 35 or fewer repeats — typically 15 to 20 — and no chance of developing Huntington disease. People with 36 to 39 repeats might develop HD, sometimes starting later than usual, and progressing more slowly. With luck, they might never be affected at all. People with 40 or more repeats will develop HD, if they don’t die of something else first.