Mark looked at me shyly through his oversized Elvis Costello–style glasses. Was he feeling embarrassed by his own reply or just waiting for my reaction? He was sitting between his mom and dad, wearing a t-shirt with a huge Minion print. His braces showed when he smiled, something he does often in a disarming way.
Over more than 20 years of working in the field of hereditary cancer as a clinical geneticist, I have witnessed many scientific developments and have met thousands of patients and families who were referred for genetic counseling. Routine becomes inevitable, but every now and then, there is someone or some family that sticks in my mind. Cycling home from the hospital at the end of that September day, I tried to figure out what it was in Mark’s story that had moved me.
I first met this bright teenager, together with his parents, when he was referred by his general practitioner (GP) to our Family Cancer Clinic for genetic counseling and DNA testing. A genetic trait runs in the family that causes skin tumors, gynecologic problems, and kidney cancer. They know how the family history has evolved over the past 5 years and that Mark’s mother carries a fumarate hydrase mutation that causes hereditary leiomyomatosis and renal cell cancer (also known as HLRCC).1
Growth of Genetic Counseling
In the past 25 years, the notion that cancer can be hereditary has moved from an academic discourse among geneticists to mainstream modern medicine. The option of genetic counseling and testing is now part of many protocols in clinical oncology. What has made the difference and rewritten the script of patient-doctor interactions in hereditary cancer is the discovery of the BRCA1 and BRCA2 genes. Suddenly, a cancer that is all too common and, therefore, familiar to almost everyone could be hereditary, and it could affect you, your mother, or your cousin. The broader result is that people are now familiar with the concept that any cancer can be hereditary.
Jan C. Oosterwijk, MD, PhD
Another consequence of the discovery of the BRCA genes is that breast surveillance and preventive surgery have become options available to proven mutation carriers. This means that a genetic predisposition is no longer synonymous with ill fate; it has become something carriers can act upon. Angelina Jolie’s revelations of her preventive surgery were the finishing touch that further increased public awareness.
It is this actionability that led Mark’s mother to ask their GP for a referral for genetic testing. Mark’s mother had her uterus removed 3 years ago, and her kidneys are screened every 6 months. Mark is 13 years old and has always been in good health, but he has been suffering from headaches lately. His mother is worried, because Mark’s cousin died of renal cancer a few years ago at the age of 18, and this event still echoes through the family. I cannot help noticing that Mark’s 18-year-old sister is absent at this first consultation. I know she has not been tested.
I try to divide my attention between Mark and his parents and seek to adapt my language to that used by teenagers. Does it help that I have kitchen table conversations with my own, slightly older, kids? Things are “chill” or “uncool,” jeans must be skinny, and social media is the world as they know it. His parents are worried, but what is Mark’s point of view? Has he given much thought about it? Can Angelina Jolie be a role model for a 13-year-old boy?
“So Mark, can you tell me what you know of this disease that runs in your family?” I take off my reading glasses, smile like he does, and try not to make it sound like a test. Mark quickly looks at his mother, who nods encouragingly. Mark starts to tell me what they had been discussing at home: that his uncle is being treated for painful skin problems, that his mother had an operation, and that the death of his cousin had a large impact on the family. He knows that before he is 18 he will have to start with some kind of medical checkup. “That’s why we’re here,” he says. And yes, he thinks this genetic thing is a bit scary. His parents are listening while he speaks, and I think I see a mixture of pride and sorrow in their expressions.
I compliment Mark on his description. “It must be a tough decision to make for the three of you,” I continue after a short silence. They all agree but in slightly different ways. Mark’s father just nods. Mark nods as well, and then adds, “Yes, but it has to do with the periodic checkups.” His mother continues by stating that they actually feel there is not that much choice at all: “Whether it’s done now or in 3 years’ time, Mark eventually has to be tested.”
Testing and Timing
His mother is right; it is not so much about testing as about timing. According to Dutch law, for children younger than age 12, the parents decide for their child. After age 16, the child may make medical decisions for him- or herself. With Mark, we are operating in the gray area between ages 12 and 16, where medical decisions should be made in the light of a consensus between the child and parents. I ask about their differences in attitude toward DNA testing, but fortunately, there seems to be a genuine consensus in favor of it.
I share with them the latest recommendations that suggest surveillance should start from approximately the age of 10 years. I show them graphs and explain they indicate the chance of finding something bad before the age of 20 is small. “But it’s not zero,” Mark’s mother says, clearly referring to her nephew.
She is right, and I try to clarify that we are discussing single-event probabilities2: When a cancer occurs, you do not get it for a few percent; it is either all or nothing. However, I add that we have no indication that Mark’s risk is higher because of the affected cousin. “We still think it’s only a few percent,” I tell them, fully realizing this estimate has a low Cochrane content. For rare genetic disorders, the denominator is often far too small to give a reliable estimate, let alone a proper genotype-phenotype correlation. We will get there eventually, but Mark may be 28 by then.
How much information can I pack into one counseling session? My probing questions reveal they are well informed and have considered the issue seriously. When I touch upon the fact that being a mutation carrier could also be important for Mark when he starts thinking about having kids, he rolls his eyes. I smile at him and decide that, for now, this information will suffice.
As I fill out the forms, I casually ask about Mark’s sister. His mother tells me her daughter does not want to be tested, not even after all their serious discussions. “She’s a different child, you know,” she adds. I suggest we should come back to this at a future appointment.
Presymptomatic DNA testing protocols have evolved to include psychological assessment and counseling, predominantly based on experience with families affected by incurable neurodegenerative disorders such as Huntington chorea. In hereditary cancer predispositions, however, prevention and treatment are the main reasons for DNA testing. Therefore, patients may choose to learn their result at an appointment in the clinic or by letter. If the test is negative, there is usually no need for further appointments, and follow-up by phone will suffice. If the DNA test is positive, an appointment is scheduled within a few days.
The large majority of patients choose to receive their result in a letter.3 They explain that they prefer to have their primary emotions on learning the result in their home setting with their loved ones. And, in more than 50% of those tested, it saves them an extra visit to the hospital. Mark and his parents chose to receive the test result in a letter sent to their home, and their GP was sent a copy.
So Mark now sits before me again with his parents. Because this is our second appointment, you can guess his DNA result. Yes, he carries the mutation associated with skin, kidney, and gynecologic problems. Yes, the family was emotional when they opened the letter together; they had so much hoped for the other outcome.
Mark’s simple summary moves me. “It is what it is,” he replies when I ask him about the result. He knows it is not cancer and that he is not a patient; he merely has a predisposition. And he knows it will not go away. I tell Mark that this phrase indeed summarizes the situation clearly and sensibly. We will arrange for a specialist who knows about hereditary leiomyomatosis and renal cell cancer to see him and take care of the longitudinal follow-up. The time for action is now.
A genetic predisposition is no longer synonymous with ill fate; it has become something carriers can act upon.— Jan C. Oosterwijk, MD, PhD
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Cycling to the hospital several weeks after I had first written about this case, I had a clearer picture of what had moved me and what I had learned. On this day it is time for the scheduled follow-up phone call. Mark’s mom answers my call, and I ask her how they have been doing. She tells me things are okay, hereditary leiomyomatosis and renal cell cancer is not actually a daily issue, and Mark is doing just fine. As for his sister, they would now like to have an appointment for her sometime in the coming months. Mark’s results and the fact that DNA can now be tested in saliva instead of blood have tipped the balance for her. It turns out she is terrified of needles and injections.
At the end of our telephone conversation, I tell Mark’s mom that I was moved by the way they handled the situation together as a family and that I have been trying to put my reflections on paper to perhaps publish as an article. I go on to say, “I was impressed by how you, as parents, gave Mark space, making him the real center of the consultation; how well informed he was on this difficult and scary subject; and how his autonomy was respected regarding the decision-making throughout the process. His summary of the DNA test result—it is what it is—showed an admirable combination of resignation and militancy. And all this at the age of 13.”
Mark’s mother is silent for a while and then replies that she feels this is a huge and unexpected compliment, stating, “This has been so hard, doctor; I’m sure you know.” I reply that I think I do.
New Category of Patients
In oncology, we are used to dealing with patients with cancer and those who have survived, who often have to deal with late adverse effects of their treatment. We witness the huge psychological impact of a cancer diagnosis, and in children and young adults, we see how it accelerates their maturation.
Presymptomatic DNA testing has introduced a new category of patients—those who do not have cancer but are at increased risk. They have been through the process of making a decision about DNA testing. When at risk, they may opt for surveillance, preventive surgery, or other ways to reduce their risk. Their frame of reference may be well known, as in BRCA; it may be less familiar, as in Lynch syndrome; or it may be obscure, as in hereditary leiomyomatosis and renal cell cancer.
These patients have to deal with understanding risk estimations, evolving screening protocols, the fear of cancer, family dynamics, and often, worries and considerations about (future) offspring. The fact that their screening appointments frequently take place in cancer clinics is confrontational and unpleasant; they do not have cancer; they are the ones who are just at a higher risk.
They may be middle-aged adults, young adults, or children, and we know their numbers will grow as we learn to recognize new genes and syndromes that confer an increased susceptibility to cancer. A looming challenge for the field is to provide adequate guidance based on evidence, resources, and, most importantly, the preferences of the patient. ■
Dr. Oosterwijk is a clinical geneticist at the University of Groningen, the Netherlands.
1. Menko FH, Maher ER, Schmidt LS, et al: Hereditary leiomyomatosis and renal cell cancer (HLRCC): Renal cancer risk, surveillance and treatment. Fam Cancer 13:637-644, 2014.
2. Gigerenzer G, Galesic M: Why do single event probabilities confuse patients? BMJ 344:e245, 2012.
3. Voorwinden JS, Jaspers JPC, ter Beest JG, et al: The introduction of a choice to learn pre-symptomatic DNA test results for BRCA or Lynch syndrome either face-to-face or by letter. Clin Genet 81:421–429, 2012.