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NOVEMBER DECEMBER 2016 #33 THE MAGAZINE OF THE FRENCH NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH Genetic tests Do we have to be able to predict everything? #33 EDITORIAL Genetic tests, a delicate balance ©Inserm/ François Guénet Since its early days, human genetics has been characterized ine Cather in a Bourg cist and geneti sociologist rche médecine, reche Centre de té, santé mentale an s , s e c scien Center for (Research ental té ié c o s t e Science, M Medicine, Society) h lt Hea & #33 November - December 2016 Subscription free, write to: [email protected] Inserm, 101, rue de Tolbiac 75654 Paris Cedex 13 www.inserm.fr by a clash between a deterministic approach and one more based on analysis of complex physiological mechanisms interacting with their environment. While the first points out the importance of the innate and goes together with a need to predict and select, the latter—closer to fundamental biology—is less conducive to prediction. And clinical genetics which only became established after the Second World War grew up against a background of seeking balance between these two extremes, i.e. to accept a form of meaning that allows action (the diagnosis, management and prevention of disease) while making efforts to control utilization to prevent abuse. High-throughput technology is changing the world of genetic testing. This world is being driven by heavyweight investors supporting a robust industry (machinery, information technology). It is becoming relevant in a growing number of disciplines from oncology to cardiovascular disease. Private companies are directly offering tests to consumers ... In parallel, new data is building up to cast doubt on assumptions that were once believed to be well-founded. Correlations between genotype and phenotype are becoming more complicated and often less sure. Determining conditions for action, lines of conduct, that are compatible with the two approaches in human genetics; that is the biggest challenge right now. Because this science has and always will have effects on how people and societies see themselves and their futures. Director of publication Yves Lévy Director of writing Arnaud Benedetti Chief Editor Yann Cornillier Writing Assistants Coralie Baud, Marie-Charlotte Ferran Headlines Julie Coquart Editorial Assistant Coralie Baud Collaborators on this issue: Alice Bomboy, Françoise Dupuy Maury, Alexandra Foissac, Stéphany Mocquery, Charles Muller, Pascal Nguyên, Agnès Noël, Julie Paysant, Hélène Perrin, Simon Pierrefixe, Vincent Richeux, Nicolas Rigaud, Bruno Scala, Mehdi SixGraphic design Primo&Primo Art Direction Myriem Belkacem, Primo&Primo Symbols Cécile Depot Cover credits Illustration: Florent Hauchard Printer Aubin Imprimeur ISSN No.: 2119-9051 Legal submission: November 2016 This product is 100% recycled. 3 4 #33 #33 Close-Up GENETIC TESTS Do we have to predict everything? piled by Report com boy om Alice B Genes cannot be seen by the naked eye but they are what makes us what we are—the color of our eyes, how tall we are, the chance that we will contract such and such a disease. Because genes carry such precious information, they have long fascinated scientists. Notably, scientists try to decipher their language to find out what each gene does. Getting genes to talk is the aim of genetic testing! Their purpose? To reveal special features that might help diagnose a pre-existing condition, personalize treatment or even predict the chance of developing some disease in the future. 5 #33 D oes that gene determine how hairy we are? That one the color of our skin? Does it act alone to determine this trait or in concert with other genes? Can some genes present in an abnormal form cause disease? Can the imminent onset of disease be predicted by looking at genes? These questions point to the very essence of genetic testing. To find answers, you have to dive into the world of genetics. For that, nothing better than the Human Genome Project, one of the most ambitious scientific endeavors ever undertaken. Launched in 1990, the goal of the Project was to sequence the entire human genome, meaning determine the sequence of all our nucleotides, the basic sub-unit of our DNA. All of our 70 billion cells contain this DNA. This molecule consists of two linear strands that wrap around one another to form a double helix. It carries crucial information including directions to form an organism as well as how said organism will grow, function k The Guthrie test has been detecting serious disease for more than forty years. grand angle and even reproduce itself. The famous Genetic tests ... before genome, i.e. the set of all of our genes genes! which is unique to every one of us. If all Where is genetic testing in all this? Histhe DNA in a single cell were stretched tory shows that the very first such test out, it would be two meters long! It is was developed as early as the beginning this long ribbon that scientists from the of the 1960s. "So long before any DNA International Human Genome Project had ever been sequenced or we could Consortium went over with a fine tooth define which genes are involved in cercomb. In 2003, thirteen years after this tain diseases! This test was—and is— monumental work started, the first results were published. "We now know that designed to diagnose a metabolic our DNA contains 20-25,000 distinct disease, phenylketonuria, that causes fragments which we call genes" says serious intellectual deficiency in newFrançois Eisinger, a physician at Institut born babies" explains François Eisinger. Paoli-Calmettes who specializes in canDeveloped by the American Robert cer prevention and screening at Sesstim Guthrie, it involves testing a droplet of in Marseille, and member of the Inserm blood taken from the baby's heel. At Ethics Committee. For the scientists that time, scientists did not know that involved, including French researchers the PAH (phenylalanine hydroxylase) at Genoscope (the national sequencing gene is central in the development of this center), this is a great disease. But they success. For those inhad understood that "Our DNA contains terested in defining abnormal function the genetic etiology 20,000 to 25,000 genes" of an as yet unknown gene resulted of certain diseases, in under-expression the immense mining of an enzyme called phenylalanine hyjob to understand thousands of genes is droxylase. What does this enzyme do? only just beginning! It breaks down phenylalanine, an amino acid that is a precursor for compounds that are essential to normal bodily physiology. In the absence of this enzyme, phenylalanine builds up in the blood and brain, causing problems with mental development. To detect the disease, the concentration of phenylalanine hydroxylase in the blood is measured. Some of today's genetic tests are still based on the same principle: since a gene's job is to guide protein synthesis, it can be shown to be working properly by checking that its product is present at normal levels in the body. But nowadays, specialists not only know how to assay gene products but also how to analyze the genes themselves. They can "read" our DNA and thereby determine where one person's sequence differs Amino acid. Basic sub-units that make up proteins François Eisinger : Inserm Unit 912/IRD – Aix-Marseille ©©Phanie/Garo 6 Université, Sciences économiques et sociales de la santé et traitement de l’information médicale (Sesstim), Cancer, biomédecine et société (CanBioS) J.P Brosco et al. Pediatrics, December 2013; 132 (6): 987-9 #33 from other people's. These alternative DNA sequences are called "variants". In practice, 99.9% of the genome is identical in all people; only 0.1% can carry variations. "Variants are the basis of our polymorphism. They define traits that are specific to individuals and explain why we are all different—because different versions of a given gene can be found in different people" explains Catherine Bourgain*, sociologist and geneticist at the Centre de recherche médecine, sciences, santé, santé mentale et société (Research Center for Medicine, Science, Mental Health & Society) in Villejuif. For example, eye color depends on which variants of the genes that control this trait are expressed. French laboratories have developed tests for 1,531 different diseases At the heart of these tests: variants What about diseases? It is by studying the frequency of a variant in a sample population of patients and then comparing it to the corresponding frequency in a sample of healthy people that scientists determine whether a variant is associated with a disease or not. The ultimate goal is to be able to calculate the risk of developing said disease."it is a complicated job. Even for single gene disorders in which there is only one gene to study, it may be found in the form of hundreds or even thousands of different variants! Of all these, which carry a risk of developing the disease and which do not? The process is long from a scientific point of view and difficult for patients to understand: on the Catherine Bourgain: Inserm Unit 988/CNRS/Université Paris-Descartes – EHESS, CERMES 3 * See S&S No. 13, "DNA: superstar or supercop", p. 46 AT THE HEART OF OUR CELLS, OUR GENES Ribosome Cell RNA GENE A Variant 1 Protein Heterozygous for gene A GÈNE A Variant 2 Chromosome inherited from Father/Mother GENE B Variant 1 ©©Inserm / Alexandra Pinci DNA 23 chromosome pairs Homozygous for gene B Nitrogenous bases of DNA Nucleus Everyone carries two copies of each gene, one on each of the two chromosomes in each pair. These may be exact copies or they may be different variants. If the two copies are the same, the carrier is said to be homozygous for that gene; if they are different, the carrier is a heterozygote. k k Every one of our cells contains 23 pairs of chromosomes. These double helix DNA structures are what carry our 20-25,000 genes. When the double-stranded DNA is copied into single-stranded RNA, the ribosome (a complex of different molecules) reads the information encoded in the gene and translates it into the corresponding protein. 7 #33 "Genes are not the whole story: they are necessary but not sufficient to trigger a disease" have no impact at all! "Some of these genetic tests are essential but their results cannot always be taken at face value" confirms Catherine Bourgain. "Take the case of a single gene disorder for which a single gene has been identified as highly associated with onset of the disorder. Nevertheless, there are people who carry the mutant gene who never develop the disorder in question. For example, take celiac disease, a chronic gut problem triggered by the ingestion of gluten. 80% of victims carry a certain variant but the same version of the gene is found in ©©Inserm/Bertrand Jordan k DNA read in a sequencer: each different color represents a nucleotide. It is read from top to bottom. How to detect a variant? One of the methods used is that of the DNA chip which is based on base-pair matching in the doublestranded DNA molecule. Bases— organic, nitrogen-containing compounds—can be considered as the fundamental sub-units of our genome. Special properties: they complement one another in DNA chips can be used to analyze gene pairs; when thymine, one of the expression in a cell. four bases, is present on one of the two strands, it binds with adenine (another of the four) on the other strand. Similarly, cytosine and guanine (the other two bases) bind one another. The purpose of a DNA chip is to locate variants present in the genome, i.e. alternative sequences of bases. The chip carries single-stranded DNA consisting of bases corresponding to the gene being probed or a particular variant of the gene. The subject's DNA is separated into single strands, labeled with a fluorescent marker and brought into contact with the chip; if the variant is present, it will bind to the chip through its complementary base sequence. Then it suffices to locate where the fluorescent signal has bound to the chip to identify which variant is present in the genome. k one hand, variants that cause a disease are not immediately obvious at the outset of investigation and on the other, we do not always know anything about the role of the unusual variant that we just discovered" explains Laurent Villard, neurogeneticist in the Marseille Unit of Medical Genetics & Functional Genomics. The presence of one variant rather than another does not necessarily mean that it is associated with disease. Some unusual variants grand angle ©©Inserm/Nicolas Degauque 8 people who are not in any way affected. So the genes do not tell us everything. In many cases, the gene is "necessary but not sufficient" for a disease to develop". A genetic test sets out to define such variants of a DNA molecule. Some of them also involve screening for abnormalities affecting either the number or configuration of the chromosomes. Diagnostic tests But when to order a genetic test in practice? Tests classified as diagnostic that investigate the causes of a disorder are the most common. "These are ordered if some symptom is observed that could point to some hereditary disease. However, diagnosis is never posed on the sole basis of the result of such a test; these tests are simply one of a number of tools and other examinations will be required. However, a conclusive result usually rules out erroneous differential diagnoses" explains François Eisinger. Such tests are especially useful for single gene disorders caused by abnormality in just one gene. One such is cystic fibrosis. Every year, 200 babies are born with this disease in France. The cause is a mutation on chromosome 7 that renders non-functional a protein, Cystic fibrosis transmembrane conductance regulator (CFTR), found in the membrane of cells in various mucous membranes. The consequence is that less water is pumped across the mucosa and the mucus that covers it becomes too thick, thereby inhibiting digestive function and breathing. Of course, the Laurent Villard : Inserm Unit 910 – Aix-Marseille Université, Human Neurogenetics Screening unborn babies Diagnostic tests can also be carried out on the fetus before delivery. "These socalled prenatal tests are usually ordered after conception when one or both parents is known to carry a genetic abnor- Immunofluorescent labeling of CFTR (red) in human alveolar epithelial cells. Left: Normal CFTR located at the cell's borders (dark red). Right: mutated CFTR from a patient with cystic fibrosis is only found in the endoplasmic reticulum around the nucleus (blue). k diagnostic test focuses on the CFTR gene. Many mutations of this gene are known, some 2,000 in number, but the one referred to as Delta F508 is the most important. The goal of the test is to pin down which mutation is involved. "Before a disease can be treated, you have to know what the disease is—it's an essential preliminary. Genetic tests not only make it possible to diagnose certain diseases but also in some cases tell us about which particular form of the disease the patient has (i.e. which specific mutation is involved) and therefore how best to treat it " explains Perrine Malzac, consultant specializing in genetics and coordinator of the Espace Éthique Méditerranéen (Mediterranean Ethical Space) in Marseille. Another single gene disorder that can be diagnosed by means of a test is hemochromatosis. Although it is little known, this is the most common hereditary disease in France, affecting one in 300 people. It causes tiredness, joint pain and a gray complexion. It is due to excess iron in the body and leads to complications like cirrhosis, diabetes and heart problems which tend to get worse with time. Fully 90% of cases of hemochromatosis are due to a specific mutation in the HFE gene which interferes with how iron is metabolized. In this case too, the test is valuable because effective treatment modalities exist to correct the underlying iron storage problem. "Specifically, diagnostic genetic tests have revolutionized the medicine of rare diseases, i.e. those that affect fewer than one person in 2,000. Now we can care for these patients better, help them and more effectively mitigate the adverse consequences of certain diseases. Of course, we do not always manage to sort everything out but we can at least explain to patients what is causing their problems. This is important from a psychological standpoint and also means that they can get access to targeted help once their disease has been defined. " ©©Inserm/Pascal Touvé #33 mality that could be transmitted to their offspring" explains Michel Favre, former Inserm Research Director. Such a test might also be ordered if the fetus seems In France, pre-implantation diagnosis is carried out for 175 diseases to be developing abnormally. This might be due to Down syndrome, a congenital problem associated with the presence of an extra third copy of chromosome 21 (trisomy 21) in the genome. Prenatal screening for trisomy 21 usually depends on assaying certain markers in the mother's blood coupled with an ultrasound examination of the fetus, interpreted in the light of the age of the mother-to-be. In some cases, evidence from this preliminary screening process indicates amniocentesis, i.e. taking a sample of the amniotic fluid in which the fetus is suspended during pregnancy. The sample is taken using a needle and the test involves microscopic examination of chromosomes in the fetal cells. Although the result is definitive, this procedure is an invasive one and can cause miscarriage. These days, it is possible to find fragments of fetal DNA in the mother's blood. These fragments derive from the placenta, a tissue that derives from the same source as the fetus (the fertilized egg) and which therefore has exactly the same genetic profile as the unborn baby. Therefore, there is an alternative to amniocentesis, namely a simple blood test in the tenth week of pregnancy. Although this form of screening for trisomy 21 is as yet relatively rarely practiced, its use can be expected to spread quickly and sampling the mother's blood to analyze the DNA of the fetus is already routine in at least Congenital disease. Disease present at birth Perrine Malzac: UMR 7268 CNRS/Aix-Marseille Université/EFS, Biocultural Anthropology, Law, Ethics and Health Michel Favre: former Inserm research Director and Head of the Genetics, Papillomavirus & Human Cancer Unit at Institut Pasteur in Paris, President of the charity Pro Aid Autisme M. E. Norton et al. NEJM, 24 December 2015; 373 (26): 2581-2 9 #33 two situations, i.e. to determine the baby's gender if there is a risk of Xlinked disease, and to determine the status of the fetus vis-a-vis the rhesus system if the mother is rhesus-negative and therefore there is a risk of incompatibility between mother and baby. Another form of disease that can be diagnosed prenatally is neonatal epilepsy (referred to as early infantile epileptic encephalopathy) that onsets in the first days of life and can result in the child's death. This condition can have various causes, including an accident at the time of delivery and cerebral malformation but also genetic mutation although this possibility is only raised once other causes have been ruled out. Although epilepsy can often be treated, doctors do not yet have any targeted treatment modalities for disease caused by mutation of any of the fifty genes known to be able to cause early infantile epileptic encephalopathy. Against this background, genetic testing may be proposed to parents who have already had a 260 diseases are addressed in prenatal diagnosis child with neonatal genetic epilepsy and who are planning another baby or are already pregnant. "In this case, our job is to provide solid information for the parents and prescribers with a view to possible testing of the developing fetus (with the parents' permission). If the same mutation is found, abortion may be considered" explains Laurent Villard. Genetic tests may also be relevant to diseases like autism. "However, care is Rhesus. Molecule expressed on the surface of red blood cells that determines one of the blood groups. Eugenics. Theory that human populations ought to be selected on the basis of the laws of genetics Hemoglobin Iron-containing protein found inside red cells in the blood, responsible for transporting molecular oxygen from the lungs around the body. grand angle muscular dystrophy (hereditary diseases warranted: I know of no genetic test that that respectively affect the muscles can predict autism in the general population! Start-up companies have anaround the pelvis or shoulder). In 2014, nounced such tests in the past but we are 645 couples were eligible for PGS and still waiting …" warns 135 babies were born Michel Favre, President following the selection “Prenatal testing of the Pro Aid Autisme of normal embryos. PGS remains highly charity that creates is tightly regulated in reception and special In June 2016, exceptional and is France. education centers for there were only hospipeople with autism. In not systematically tals authorized to carry it out in five regions (Alpractice, only a minority proposed" sace, Île-de-France, of cases of this disease Languedoc-Roussillon, are caused by a single Pays de la Loire and Rhône-Alpes). gene. So far, scientists have identified a whole series of mutations linked to this disorder but every one of them is rare, Help for better care affecting just one patient or at most a Among the battery of tests available handful. But even in these cases, knowing about the mutation is of genuine today, some are also therapeutic, i.e. value. "For a couple who have already had an autistic child, the identification of a genetic mutation that could have caused the problem means that a prenatal test could establish if an unborn child is carrying the mutation in question. And therefore the risk of the child developing the disease. It is important A disease is described as genetic to realize that such prenatal testing reif it is caused by one or more mains highly exceptional and is not sysabnormalities on one or more tematically proposed" explains Michel chromosomes that impair how cerFavre. Another advantage of these tests tain cells function. Not all genetic is that they make it possible to provide diseases are hereditary (i.e. transbetter monitoring for children carrym i t t e d t o p ro g e n y ) b e c a u s e ing the mutation so that the developing the mutation responsible may problems of autism can be tackled as not necessarily be present in the early and as effectively as possible. cells of the reproductive systems that give rise to eggs and sperm What about couples who are aware that i n w h i c h g e n e t i c i n fo r m a t i o n they are carriers of a serious genetic disis transmitted. In contrast, all ease before they conceive, and want to hereditary diseases are by definiblock transmission to their progeny? tion genetic! A familial disease is They may have access to pre-implantaone that affects different members tion genetic screening (PGS) in which of the same family. the genomes of embryos resulting from in vitro fertilization are screened to identify the genetic abnormality in question and only "normal" embryos are selected for implantation. For ethical reasons—and to preclude drift towards some form of eugenics —not all diseases are eligible for PGS; only serious, incurable pathologies with a high transmission rate (25-50%). Dozens of diseases do meet these criteria, including cystic fibrosis, thalassaemia, a range of hereditary blood disorders characterized by defective hemoglobin synthesis and limb-girdle or facioscapulohumeral Hereditary, genetic, familial: what is the difference? ©©Fotolia 10 k By means of testing, the geneticist can tell a couple what the chance is that a given genetic disease will be passed on to their children. designed to help match treatment strategy to the patient's genetic profile. Such tests are designed to predict how the body is going to respond to a drug with a view to anticipating possible adverse reactions, the risk of overdose and simply whether or not the drug will be effective in specific patients. The principle? This means identifying genetic variants associated with drug absorption and metabolism (conversion and breakdown) with a view to predicting what will happen to a drug inside the body and therefore how active—or inactive—it is likely to be. For example, no patient should be prescribed a drug to which he/she might be particularly sensitive and which might therefore trigger serious adverse reactions. This is the principle that underlies a test that looks at polymorphism in HLA genes in the Major Histocompatibility Complex, the system that controls the recognition of self on the basis of molecules expressed on the surface of cells. Certain variants of these genes are associated with hypersensitivity to abacavir, an antiretroviral drug used in the treatment of HIV infection. In cancer treatment, genetic tests ©©Fotolia/Stockphotopro #33 are carried out on tumor DNA which is mutated with respect to the inherited DNA found in non-malignant cells. Identification of these mutations in the tumor makes it possible to target the cancer cells more specifically. Genetic testing can also save money. Treating metastatic cancer can prove extremely costly but genetic analysis can ensure that a tumor will be more specifically targeted by a given treatment modality. This type of cancer which is characterized by a capacity to spread from its original focus to other parts of the body often leaves care-providers at a loss. How to treat cancer growing in different tissues? Because usual strategies often fail, innovation is key. This is the goal of Christophe Le Tourneau , a medical oncologist who is directing preliminary trials at the Institut Curie. In 2012, scientists launched SHIVA, the first clinical trial exclusively focusing on the biological profile of tumors irrespective of location. "A persistent dogma has it that how a tumor should be treated depends on the organ in which is arose. SHIVA opens up another avenue: if a given treatment modality is effective against a given form of cancer, why would it not be so against a tumor in a different place carrying the same molecular abnormality. " explains the researcher. The principle of the trial is simple: rather than looking for abnormalities related to the tumor's original location, such as mutations in the receptor for Epidermal Growth Factor (EGF) in lung cancer, screening is expanded to cover all abnormalities for which targeted therapies** are available, whatever the type of the tumor and its location. A genetic map of the tumors is thus established, based on the mutations that they show. The trial being conducted on a thousand patients is focusing on some forty tumor types. The first results are already out. Firstly, the genetic map of the tumors can be drawn up fairly quickly—within four weeks—so treatment can be adapted soon. Moreover, efficacy results indicate prolonged progression-free survival in certain groups of patients on targeted therapeutic regiOf all the genetic tests carried out in France in 2015, 19,909 were therapeutic in nature mens. With these encouraging findings, an extension study, SHIVA 2., has been set up to confirm this precision medicine approach in a group of patients in whom the tumor's MAP kinase system is impaired. These kinases are proteins that control cell division for which targeted treatment modalities exist. In 2013, the Institut national du cancer (INCa, National Cancer Institute) launched the AcSé (Accès sécurisé à des thérapies ciblées innovantes, Secure Access to Innovative Targeted Therapy) Christophe Le Tourneau: medical oncologist and responsible for early trails at Institut Curie ** See S&S No. 14, Close-Up "Personalized medicine. the promise of tailor-made treatment", pp. 22-33 11 grand angle #33 Program. "Both of the trials we are conducting, namely AcSé crizotinib and AcSé vemurafenib have the same goal: to gauge whether an innovative drug that is already licensed for prescription can be effective in patients with cancer in a different organ that is expressing the abnormality that is targeted by the drug in question. The aim is to expand the scope of prescription for innovative drugs and then assess their efficacy" explains Natalie Hoog-Labouret who oversees the Drug Unit of INCa and is coordinating the Program. The third trial, AcSé-ESMART, launched in June 2016, offers children in therapeutic failure a treatment regimen that takes stock of the abnormality detected in their tumor, based on drugs in development (some- times still in the early stages thereof) for cancer in adults. " Predicting disease? ©©L. Neal/AFP Photo 12 k After the actor Angelina Jolie announced that she had chosen surgery in 2013, the number of women getting tested for BRCA1/2 rose in a number of countries. Above and beyond diagnostic, pre-implantation and therapeutic tests, there is another type of genetic test that often hits the news, namely the predictive test. In 2013, the actor and director Angelina Jolie announced that she had undergone preventative double mastectomy (surgical removal of both breasts), followed two years later by removal of her ovaries and Fallopian tubes. The reason for these operations? She had found out that she was carrying a genetic mutation that predisposed her to develop cancer in the future. Some years earlier, she had lost her mother who had suffered from cancer of the breast and ovaries. Her grandmother has also died of ovarian cancer. Now we know that some of these "hereditary" cancers that strike different members of the same family are linked to an abnormal variant of the BRCA1 (Breast Cancer 1) or BRCA2 (Breast Cancer 2)gene. For Angelina Jolie who carries an abnormal copy of the first of these two genes, doctors calculated her risk of developing breast cancer in the future at 87%, and that of ovarian cancer at 50%. That is why she opted for surgery. This story raises a number of questions. Notably, what do you do about a risk? Does carrying an atypical variant of a gene involved in cancer mean that the carrier is definitely going to contract that malignancy? The answer is far from simple. For example, in breast and ovarian cancer, BRCA1 and BRCA2 both code for tumor suppressors, meaning that the protein that they code for helps repair damaged DNA. When this gene is mutated in certain ways, its product can no longer do its job properly. This can lead to the growth of a tumor and ultimately lead to cancer. But caution is warranted! Not all mutations in these genes are harmful: not only are there thousands of different mutations possible in these genes but also some of them can even enhance the host's ability to fight cancer! A study conducted in 2011 at the University of California in San Francisco came to the conclusion that some polymorphisms can be protective ... The complicated concept of "risk" In fact, the cases in which a genetic mutation has any effect on the development of disease are relatively rare, essentially concerning single-gene disorders such as Huntington's disease (see Box). In many diseases, genes are not the only issue: exposure to environmental factors and behavioral traits also affect the incidence of mutation and therefore development of the disease. "There is a genuine understanding problem in this area. We mistakenly believe that, once a link has been established between a dis- 2 women in 1,000 carry a mutated BRCA1/2 ease and a gene, mutation of said gene is synonymous with pathology. Genetic tests sold on-line ignore any gray areas and push a single idea: a mutated gene is equivalent to disease. But it's far more complicated than that!" affirms Catherine Bourgain. Understanding exactly what risk means is crucial when it comes to predictive genetic testing. A predictive test aims to determine the excess risk—compared with the population as a whole—that someone has of developing a disease because they are carrying some genetic marker, e.g. a specific mutation in their BRCA1 gene. But between the risk in the general population and that in a specific individual, there is an ocean! "At the individual level, the risk of developing a disease doesn't mean much: you either have it or you don't! The risk in the general population may well be 30% but if you have the disease, you're not 30% sick but 100% sick" points out Perrine Malzac. In some cases, the consequences of a person discovering that they carry a risk of developing a certain disease and that they might transmit it to their children C. Le Tourneau et al. British Journal of Cancer, 8 July 2014; 111 (1): 17-24 #33 13 describe this phenomenon: "Imagine that you're on a gentle slope. Without even noticing, you can pass from a legitimate idea—screening for serious, incurable diseases—to an illegitimate one which could ultimately lead to the In 1983, American scientists identified a selection of embryos on the basis of gene involved in Huntington's disease, a neurodegenerative condition that causes highly controversial criteria. There are major, severe impairment of physical and no fixed boundaries here and it's difintellectual capacities. There is currently no ficult to know when to say 'Stop'!" he treatment for this disease. It was the first Mutation of huntingtin explains. Analysis of fetal DNA in the time anywhere in the world that a gene had leads to the formation of mother's blood has attracted the attenbeen definitively shown to be linked to a disease! tion of the Agence de la biomédecine abnormally long primary What put the scientists on the genetic track was (Biomedicine Agency) which is responprojections on brain cells. the fact that it was inherited: if one of the parents sible for monitoring the fields of mediThis affects cerebrospinal suffers from the disease, each of their children has cally assisted procreation, prenatal and one chance in two of contracting it. The thing that all fluid flow between the pre-implantation diagnosis, and human sufferers share is that one of their genes—encoding brain and spinal cord. huntingtin—is mutated, i.e. damaged. Result: it no genetics. The Agency worries about the longer does what it is supposed to do which is what way being paved for possible future ethicauses the disease. cal problems by the fact that this method is making it ever easier to analyze the DNA of an unborn can lead to radical decisions, e.g. the And this question Many experts "When someone is sick, baby. preventative removal of organs (as in could be extended are worrying about the case of Angelina Jolie) or elective to any number of they aren't 30% sick but the potential for abortion of an unborn child. "Society different criteria problems being raised 100% sick" needs to reflect on the implications of ... " suggests Chrisby so-called predictophe Le Tourneau. tive tests. "If genetic such technology that could ultimately François Eisinger, uses a metaphor to tests became very popular, we would all lead to choosing what is acceptable and what is not in terms of a future child's genetic make-up. Does this not sound a E. Yong, Nature, 16 May 2013; 497: 297-9 bit like eugenics?" asks Perrine Malzac. Today's law considers trisomy 21 a sufficiently serious health problem to justify elective abortion. "But for those who know someone with Down syndrome, it is difficult to assert that his life is not worth living. The fact is that, if abortion is an option for this condition which is perfectly compatible with a happy life, the door is wide open for other conditions ... other "defects". In China, scientists are beginning to sequence the genomes of people with an IQ of over 160 with a view to identifying a genomic signature that is predictive of a high IQ. In the future, could parents decide only to keep children with a high IQ? k ©©Inserm/Frédéric Saudou Huntingtin, the first gene linked to a genetic disease Two markers in the blood are assayed in a blood sample taken from the mother in the first trimester of pregnancy and the results combined with ultrasound measurements are used to screen for trisomy 21. ©©Phanie/Garo k #33 come to the realization that none of us have a "perfect" genome! But it's useful to remember that we aren't ill until pathology manifests, and not before" underlines Perrine Malzac. grand angle Sampling cells inside the mouth; a simple procedure at the beginning of many genetic tests k The question of chance discoveries Another point that is exercising scientific Ethics Committees is what to do if an abnormality is discovered by chance. Imagine a geneticist is investigating a patient's exome (i.e. all genes that code for protein) for the purposes of diagnosis. But in addition to discovering the patient's genetic status vis-a-vis the suspected disease, an entirely different abnormality is detected that predisposes to a completely different disease. "Such chance observations are never easy to deal with. What does the mutation imply? Is the carrier going to get sick? When we know what to do to treat a disease, the issue is relatively simple because we can at least offer the patient treatment" explains Catherine Bourgain. To prevent such chance discoveries, some geneticists opt for caution: rather than looking at the whole exome (in which case the risk of detecting unsuspected mutations is greater), they focus exclusively on genes related to the diseases that they have been ordered to investigate. "Before, chance discoveries were rare because economic constraints coupled with technological limitations forced testers to concentrate on one or two genes selected on the basis of family history. But for some years now, examining 500—or even 23,000—genes has represented no problem! " explains François Eisinger. In France, genetic testing, like everything to do with medical genetics, is regulated by bioethics laws. These texts stipulate that the subject (or his/her representatives) must agree to a test and that he/she can refuse to be told the result of the test. On the other hand, he/she is obliged to inform family members in the event of detection of a genetic abnormality that warrants preventive or health care measures. The person's doctor can communicate this notification if the subject does not want to do it him or herself. This framework covers chance discoveries of known diseases for ©©Fotolia 14 such a job, etc. Will they really change which prevention or treatment modalities exist. But what to do if the mutation their lives, in the end? At least, it gives them the chance" explains Perrine detected is associated with a disease for Malzac. which nothing can be done to improve prognosis, as in Huntington's disease? Or if the mutation carries a small risk of Support developing a disease, such as the ApoE4 from A to Z variant (associated with damage to vessels in the brain) and Alzheimer's dis"There are no simple situations with ease. Should the subject or his/her family genetic testing which is why substantial support is provided throughout be notified? In this case, good practices the process. Discussion rules have it that it is between doctor and often decided that only patient is key" notes information deemed use"It's useful to ful by the doctor should François Eisinger. Before remember that be passed on. a test is ordered, the specialist should provide full “If tests for incurable we aren't ill information, i.e. explain diseases are available, it exactly what will happen is often because patient until pathology and all the possible consupport groups have manifests, and not sequences for the subject insisted that they be and his/her family, such made accessible for the before" as learning about a lifepurposes of diagnosis threatening condition, and also for before any need for treatment, abortion or risks to symptoms manifest, i.e. before onset future generations. Getting the subject to of any disease" notes Michel Favre. sign a Consent Form is an indispensable Because although some people prefer preliminary to placing the order. "Genetic not to know about the lethal fate that counseling plays a key role. It is the counwill catch up with them one day, others want to prepare themselves. "Some selor who, on the basis of an examination of the subject's test results and family patients whose family history suggests history, will accompany him/her during that they might be carrying a marker treatment or prophylaxis" explains Mithat is a reliable predictor of disease, chel Favre. For the subject, the testing itmight want to know so that they can self is simple: in most cases, it just involves organize their lives accordingly, e.g. giving some blood although sometimes not to have children, choose such and #33 1,577 different genes are targeted in diagnostic tests samples of skin, hair or amniotic fluid my be required. And of course, swabs of cells from inside the mouth, as popularized in crime shows! Compared with the matter of minutes that taking the sample takes, analysis is longer; depending on the complexity, results may be available within weeks or may take longer. The testing is carried out and the results interpreted at specialist facilities which are audited every year by the Agence de la biomédecine. Once the results are ready, it is important not to confront the sub- Forthcoming Genetic tests: illusion or prediction? Perrine Malzac and Marion Mathieu October 2016, Le Muscadier/Inserm, coll. "Health shock", 128 p., €9.90 ject with a completely incomprehensible report! The results are always sent to a doctor who is responsible for explaining them to the patient. A genetic test is not a neutral examination: reporting the results to the subjects requires delicacy and may entail referral to specialists. Whatever the framework of the testing, all scientists insist on certain things: "Although genetic testing helps some patients in special circumstances, we cannot and should not expect an answer to everything from genetics. Sure, the technology is powerful but its use must remain reasoned and reasonable. Some people would like to see everyone’s entire genome sequenced. but this is ridiculous although many privater companies would not hesitate to subscribe to it for venal reasons. It is important not to fall into the "everything-is-genetics" trap" concludes Michel Favre. n www.genetique-medicale.fr Visit the Agence de la biomédecine web page on medical genetics aimed at the general public To find out more: Access the documents and videos from Ketty Schwartz training seminars on genetic tests, organized by the Inserm Associations, Recherche & Société Mission: www.inserm.fr/associations-de-malades/ In issue No. 32 of Science&Santé, Yves Lévy, CEO of Inserm, presented the French Genomic Medicine Plan, Measure 13 of which addresses providing information for stakeholders in society (S&S No. 32, Strategies, p. 44). ©©Phanie/Garo/CHU Rennes k A doctor explaining the disease process to a patient at the Hemochromatosis Screening Center in the Liver Disease Clinic in Rennes. 15 FREE MAGAZINE NOT FOR SALE