by Lone Frank
“Hey, what about this?”
My boyfriend sneaks in to look at the report, and his nearsighted eyes have, of course, alighted on rs2146323. “It produces a small hippocampus,” he says cheerfully. “That can’t be good. As far as I remember, this brain area plays a role in learning and memory.”
I confirm that the small sausage-shaped structure plays a crucial and central role for both.
“You have the genotype C,C,” he says, reading aloud from the study. “Individuals with the C,C genotype display a hippocampus of less volume than bearers of T and A variants.”
He looks at me triumphantly. But I remind him that, just a couple of years ago, I had my brain scanned by some top neuroscientists at the University of California, Los Angeles, and none of them said anything about a small hippocampus.
“That’s lucky,” he says, but there’s more. “Increased risk of depression with this one – rs3761418, which is on the BCR gene on chromosome 22. Here, too, you have the G,G genotype, and they have a third greater risk for depression than carriers of the other variants.”
Before he really gets going, I click on the original publication and point out that the result comes from a study of 329 Japanese patients. “Japanese!” I say with emphasis, explaining that you need to take all this with a grain of salt. It is not necessarily the case that each of the genetic associations that are discovered and written about holds up in practice. For a finding to have weight, it must be repeated in several independent studies, and it is absolutely not the case that you can automatically infer that a result that applies to one ethnic group also applies to another.
“I see,” he says slowly. “I just think this variant is interesting in consideration of the fact that you do suffer from depression, right?”
He has a point. At the moment, I’m not medicated but, according to my psychiatrist, I ought to be – for purely preventative purposes. In the past seven years, I’ve had three depressions requiring treatment, and that is enough for them to know that, statistically, there will be more. They also know that every single episode harms the brain, and, quite apropos, one of the side effects of repeated depressions is that the hippocampus shrinks.
I’ve thought a great deal about my depressive tendency, because it clearly runs in the family. But I don’t have the energy to go into it right now, and certainly not with an uncomprehending boyfriend reading over my shoulder. Instead, I would rather look at something I know Promethease focuses on – namely, how the body metabolizes various chemicals and, especially, pharmaceutical drugs.
As it happens, specific gene variants can tell you what dose you should take for optimal effect and, at the same time, avoid toxicity and side effects. As Cariaso put it: “It is so much more important to know something about how the body metabolizes drugs than about whether you’re predisposed to Alzheimer’s, which you can do nothing about anyway. I predict that genetic tests for how any number of drugs are metabolized will soon be a part of our medical records.”
This would not be a bad idea. It is known that one in five deaths in the United States is due to faulty medication, and a good number of these are to do with doses that are too high for patients who metabolize the relevant chemical too quickly and are thus poisoned. Seen in this light, I am amazed how little deCODEme has to say about this sort of thing. The deCODEme report says I need more than 2.5 milligrams a day of the blood thinner Warfarin if I’m hit by a brain thrombosis. It also informs me that I am among those who, for genetic reasons, do not have a high risk of developing muscular dystrophy if I take cholesterol-lowering statins. Nice to know, but it doesn’t mean much in relation to the fact that, on the basis of the same raw data, Promethease refers me to articles regarding the metabolism of more than fifty named drugs.
Methadone, for example. In a single SNP in the gene for one of the brain’s special transport proteins, I have a T from both my parents, and this means I am among the three percent of the population who need more than 150 milligrams of methadone a day to counteract withdrawal symptoms from heroin. As my boyfriend notes, “It’s almost to the point that you should keep a card in your wallet.”
I’m not concerned about ever having to deal with heroin withdrawal or methadone doses, but it is worrying that it doesn’t look like I can metabolize the drug modafinil very effectively. The drug was developed to treat the sleep disorder narcolepsy, but has also been shown to be excellent at keeping healthy people awake far beyond their normal bedtime while, at the same time, increasing concentration. In fact, students and shift workers who need an acute increase in late-night cognitive ability already use it as a sort of mental doping, and I have to admit that I have more than once thought of trying it. But, according to Promethease, a single unfortunate SNP means that I would probably experience no effect. All I can do is take comfort from the fact that a quarter of the population is in the same boat.
“This is really interesting!” my boyfriend now exclaims. “Listen – there is a gene that causes small breasts if you drink too much coffee.”
At first, I think he is pulling my leg, but it’s true. The CYP1A2 gene codes for an enzyme that determines how quickly we metabolize a number of compounds, one of which is caffeine. In rs762551, there is either a C or an A, and an A creates a change in the enzyme that allows you to metabolize caffeine more quickly. I myself am an A,C and thus have an overall metabolism somewhere in the middle. “One study of healthy, fertile women concluded that those who drank tea or several cups of coffee a day had significantly lower breast volume. But only if they had at least one C in rs762551,” my boyfriend recites aloud.
I have no desire to see his smarmy grin.
“Over forty percent of women of European extraction have this mutation,” he informs me. “They should prohibit women under twentyfive from drinking coffee. It’s clearly very deleterious.”
I ignore the tasteless remark and read on myself. The researchers behind the breast volume study cite other reports indicating that coffee actually protects against breast cancer. A study of 411 women with mutations in the BRCA1 gene (of which 170 were ill and 241 healthy) focused on the connections between breast cancer, coffee consumption before the age of thirty-five, and the CYP1A2 genotype. And even though the CYP1A2 genotype does not in itself have anything to do with the risk for breast cancer, it appeared that women with at least one C variant in rs762551 who also drank coffee had a sixty-four percent lower risk than those who never drank it. Coffee had no effect on those women without C variants.
“Okay,” I say, pulling the plug on Promethease for the day. “I’m going to keep drinking as much coffee as I usually do, but you know what? I think I’m ready to have a BRCA test.”
GETTING SCREENED FOR BRCA requires more effort than sending a gob of spit through the mail. First, I have to go to my own doctor and convince her that I should be referred for genetic counseling.
“It’s probably reasonable enough,” she says, glancing over her reading glasses. She signs the form and sends the referral to the Copenhagen University Hospital.
Several weeks later, I receive a notice to turn up for a consultation – with a nurse, it turns out. A nurse who must not express herself on whether I can get a gene test or not, because her job is to find out if I even have a reason to pester the specialists. Do I have a sufficient aggregate number of cases of breast cancer in my family or am I just overexcited? She questions me patiently and takes notes on my family history. Then, she sends me home and begins to gather the available medical records about the sick and the dead. If we are lucky, she explains, there may still be a little tissue in alcohol or paraffin left from one of them, tissue that can be requisitioned from the hospital’s biobanks and tested. While this is investigated, I’m supposed to wait – for several weeks – for an appointment with the clinical geneticist, who will provide counseling, if I’m approved for it.
“It is expected that the consultation will last about an hour and, therefore, a parking pass will not be issued,” reads my referral not
ice. I bike to the hospital and find my way to the sixth floor and the department of clinical genetics. Behind the glass doors, there are no patients to be seen, only a couple of laboratories and a number of offices. My consultation is supposed to take place in one that does not call much attention to itself – discreet grey walls, the usual indeterminate institutional furniture, a noticeboard with a couple of wry children’s drawings. An experienced clinical geneticist, Dr. Kjergaard, informs me that she has advised hundreds of patients. She opens a folder with my information, puts on a professional yet cheerful tone. She seems to be in a good mood, generally.
“You’ve been referred by your doctor, I see. I’ve got the relevant papers on family matters, and we have drawn up a family tree. If you look here, men are indicated with squares and women with circles.”
It is an incredibly simple family tree for an almost pitifully small family. I am indicated at the bottom as a blank, white circle, but the two circles directly above it and connected to my own each have a large, fat line through them and a little black spot. Signs that stand for illness and death. Below that are written the dates of death, and for a moment I stare silently at the 1984 that is my mother’s.
“I presume you yourself are completely healthy?”
How do you answer a question like that? It’s impossible to know, and thanks to my genome, I’ve had my eyes opened to the fact that I am encumbered with a risk for one thing or another or another.
“So far as I know,” I finally say, whereupon Kjergaard points to my family tree.
“We have documented information that your mother got breast cancer at forty-three.”
“I’ve also just turned forty-three,” I say without really wanting to. The remark hangs awkwardly in the air.
“Your grandmother got breast cancer at fifty-seven, I can see, and your grandfather died of prostate cancer, but that is not unusual at that relatively high age. Do you know of any other instances, on either your father’s or your mother’s side?”
“No. There’s not that many of us.”
“The exercise here is about assessing whether the aggregate number of cancer cases are more than you can expect in an average Danish family.”
Kjergaard cocks her head and reminds me gently that cancer is a very frequent illness, which a third of us can expect to get at some point in our lives. No rarity, then.
“And breast cancer is the most ordinary form in women; every ninth or tenth is hit. But what can be said in your instance is that there are two direct, first-degree relatives who have had it. But to be able to say with certainty that it is something predominantly genetic and not just chance, we have to be able to see three generations, and we have to have more instances of cancer in each generation.”
It shakes me a bit that two cases are not enough, but I can’t come up with more. My maternal grandmother’s sister emigrated to the United States when she was quite young, and I have no idea what happened to her or her descendants.
“As things stand, I can’t say with certainty that there is anything hereditary at play here. But it stands out that your mother got it at such an early age.”
See, that’s what I think.
“What we do then is compare statistical analyses of families in which we’ve seen something similar and, in that case, you come out a little higher than the average. You fall into the category we call ‘moderate lifetime risk’.”
Moderate lifetime risk – what does that mean? It doesn’t immediately tell me much. In most contexts, moderate is a positive word.
“I normally don’t care for putting percentages on things, because it can be too much for some people. I’d rather put it this way: you have a far greater chance of getting through life without breast cancer than of getting the disease.”
That sounds a little evasive, I think.
“But if you would really like a number?”
I would and, at last, a piece of paper with some data slides across the table. Kjergaard shows me a simple chart marked by two curves, one of which represents the average cancer risk for women between the ages of forty-three and eighty-three and the other my personal risk during the same years. My curve rises somewhat faster than the average and, at eighty-three, it reaches twenty-three percent.
“Your lifetime risk, which we calculate on the basis of some studies and tables, lies somewhere between twenty-three percent and twenty-eight percent and, since you thereby are a little higher than the average woman, the system has a particular offer for you.”
A little higher? The phrase ricochets around the room. I know the average woman has a risk of ten percent. Further, I know we are looking at something more than a “little,” and assume that we must be getting to the BRCA test. I move to roll up my sleeve so they can take a blood sample.
“Our offer is that, from now on, you can get an annual checkup here at the University Hospital, where you’ll get a breast examination from an experienced breast surgeon, and a mammogram. For young women – uh, like you – an ultrasound examination is also performed.”
What is she talking about? An experienced breast surgeon? Here I am, sitting in the very heart of the Danish healthcare system, across the desk from one of its most prominent specialists, and their offer is to have me fondled and illuminated just like in the old days? I’m a member of the genetic age; I want a molecular insight into my situation, one appropriate to the times. It may well be that they can’t see three generations back into my family, but that doesn’t mean that they can preclude a BRCA mutation that may have arisen in my grandmother or even my mother. And which, therefore, I might have inherited.
Presumably, the experienced Dr. Kjergaard has encountered this type of mutinous attitude before, because she remains tranquil.
“If your mother had lived, we would have offered to do a BRCA examination first of her and, if she had mutations, then of you. But we normally only make that offer when there is someone living who has the disease, in order to ascertain what mutation it is. Since we are not sure whether there even is any dominant heredity factor in your family, the probability of finding a BRCA mutation in you is not particularly great. Where we typically find mutations, the family history looks somewhat different.”
I feel neither comforted nor convinced. Why not just sequence both my genes – BRCA1 and BRCA2 – and compare them, base by base, with the mutations already known that can be taken from various databases? After all, we are not talking about smashing atoms but about tossing a little DNA in a sequence machine and getting a computer to read the printout.
In fact, I’ve come prepared. I went to the Myriad Genetics homepage, which explains that, in cases like mine when you don’t already have information about particular genetic variations, the scientists there do a full sequencing and compare the client’s genes with a consensus sequence for both BRCA1 and BRCA2.If they find deviations from the norm, they can go to databases and see whether they have been described before and whether they seem to increase the risk of cancer. At the same time, they look for types of mutations that you can reckon are harmful, because they prevent a protein from being produced by the BRCA gene. The healthcare system should be able to do the same thing, I suggest, and place my printout on the table in front of my advisor.
She looks a little tense and pokes at it with one finger, then takes a deep breath before answering my question. “Our attitude is that this requires counseling. People cannot themselves interpret something like this,” she maintains. “Technically, we could easily do what you’re asking, but we would still have an interpretation problem. Our procedure is to test someone who has the disease. It is the only way we can be sure of finding a connection between the disease and any mutations. But listen: even in families where there is a large number of cancer cases and we are certain there is a dominant hereditary factor for breast and ovarian cancer, we find a BRCA mutation in under a third of those who have the disease. This indicates that there are still risk genes and mechanisms we don’t know about yet. The problem with ful
l sequencing is that you find so much you cannot definitely know the meaning of.”
“Are you saying that, if they did a full sequencing of my BRCA genes, there could be changes that you haven’t seen before?”
“There is a reasonable chance of finding something we cannot advise on, because we don’t know whether it leads to an increased cancer risk. And that message would not be much fun for you to get, right?”
No, it wouldn’t be, but neither is it fun to walk around with the feeling that there might be something that could have been caught and interpreted. I decide to press one more time.
“If I were very nervous and unconvinced by your explanation, and if I pestered you to have a full BRCA sequencing to see whether there might be something that they know about from other places …?”
The good doctor looks frazzled.
“Then, I would reply that the probability of finding anything is very small. Your family does not seem particularly at risk, and I’ve never had anyone ask in this way. But, as a starting point, if I can sense that you understand what the limitations are, I would discuss it with my colleagues.”
I concentrate on getting my puppy-dog look right. And it apparently works, because Dr. Anne-Marie Gerdes, the newly instituted head of cancer genetics, is sent for, and she agrees to hear the case and help me make a decision. She especially wants to hear whether I’ve really understood the sort of a snowball I will have started rolling if I succeed in getting a BRCA test and it actually shows known mutations – mutations known to provide a sixty-five to eighty percent chance of breast cancer. Could I handle it?
I think so. After all, I have lived with these thoughts since I was around fifteen years old. I realize what choices I will have if I discover I have any mutations. I can accept the offer Kjergaard already proposed – annual palpations and mammograms – or I can have both breasts removed and replaced by silicone implants, as Kári Stefánsson so kindly proposed. I ask whether they have any guidelines for what they are recommending.