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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?
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EDITORIAL
Genetic tests,
a delicate balance
©Inserm/ François Guénet
Since its early days, human genetics has been characterized
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November - December 2016
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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,
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Direction Myriem Belkacem, Primo&Primo Symbols Cécile Depot Cover credits Illustration: Florent Hauchard Printer Aubin Imprimeur
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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.
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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
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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.
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"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
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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.
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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
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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).
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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
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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
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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
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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
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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
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grand angle
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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
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