Thierry Frebourg: So, good afternoon.
First of all, I would like to thank the organizer for this very exciting and challenging meeting,
and it's my pleasure to present the National and Stratified Development of Genomic Medicine
in France on behalf of this National Alliance for Life and Health Science, which has been
created in 2009 in order to coordinate all the efforts in terms of health care, better
so life science research, and which is directed by Professor Olesa Repat [spelled phonetically],
present here.
So, since one critical aspect of what we are discussing during this two-day meeting is
the clinical evidence, we have considered that a top priority was rare disease and cancer.
Now, the national strategy was mostly inspired by the fact that, as you know, and as we are
aware of that, the challenge in this modern area of genetics is not in more genetic variation
detection, but genetic variation interpretation.
I think that we all agree that if we are conserving just the 1.2 of genome, of course when we
do exome, we are going to identify in each exome of the patient 20,000 SNV, around 500
are rare, not present in the database, and the big challenge, especially in the clinical
aspect, is to provide evidence that the SNV is involved in the disease.
Of course, we need very sophisticated now statistical analysis, and we are missing,
at the present time, involving our whole countries in Europe, an accurate estimate of the allelic
frequency for rare variance, which we're going to see is below 0.1 percent.
Of course we need more and more very simple animal models such as the zebrafish, but of
course it's extremely important in the confrontation of the genotype and the phenotype.
It's the reason why our strategy has been inspired by the challenge and is mostly based
on the development of national, clinical, and molecular genetics networks.
So, this has been performed within the framework of the French Plan for Rare Disease.
You know that in Europe we have around 25 million European citizens suffering from these
rare diseases, 3.5 million French citizens suffering from these rare diseases, which
prevalence can be estimated about one among 2,000.
And in France, the Parisian Ministry of Health and Solidarity and Ministry of Higher Education
and Research, the big challenge was to provide expertise, but also territorial equity.
It's the reason why the first action was -- is first of all to create a national network
of the country of what we call Reference and Competence Clinical Center for Rare Disease,
which were split in different topics, such as, for instance, cardiovascular disease,
or rare neurological disease, and we have, over the country at the present time as the
conductor of this organization, roughly 131 reference centers, which are going to coordinate
all the competence center in order to provide an expertise at the clinical level.
The second action, thanks to this plan, was the creation for rare disease of National
Networks of Molecular Genetic Laboratories all over the country, which are all specialized
in a subgroup of rare disease.
For instance, we have cystic fibrosis networks.
We have neurogenetics networks.
You will see that cancer is outside of the fields.
So this network, which has been organized through the National Organization of Molecular
Geneticists, and which is working a strong collaboration with our old research laboratories,
which are mostly located in France University Hospitals, and shows a diagnostic of roughly
1,250 monogenetic disorders corresponding to more than 1,300 gene involved in monogenetic
determinism, and this corresponds to more than 400 genetic analysis, both for index
cases and relatives.
So, we have roughly 100 molecular genetic laboratories over the countries.
In the context of the technological revolution, due to implementation of next-generation sequencing,
most of the laboratories are now being equipped with NGS platform but in the medium size format,
corresponding mostly to Miseq, for instance, a machine.
So, one important action, thanks to this French plan, was also the creation of the French
Foundation for Rare Disease, which is a non-profit private structure that coordinates, stimulates,
federates, and funds rare disease research, and it was very important, thanks to this
organization toward [unintelligible] Nicolas Levy, to facilitate access to NGS platform.
And, for instance, what has been done is to boost access to international platform of
high-throughput NGS for exome analysis, both in research fields but also in diagnostic
fields, when, of course, targeted analyses are negative.
We have, at the present time, five inter-original platforms, where [unintelligible] for exome
analysis, mostly exome analysis, some of them are genetic analysis.
There's also bioinformatic trainings and bioinformatic analyses.
And thanks to the French Plan we had to open calls corresponding to 77 funded project,
and which has [unintelligible] pair from more than 1,100 exome.
Now, in parallel, because it's quite different, but the philosophy of the organization is
the same, in terms of cancer, and that was the main achievement I think, in France, we
have a so what is called a plan cancer, cancer plan, and there's an exploration of the National
Cancer Institute, and the idea was also to organize these two floors both in the clinics
and molecular genetics of cancer -- for cancer, and for that would be organized through the
Network of the University Hospital and the Comprehensive Cancer Center.
The first floor was a network of clinical cancer genetics center, so now we have 60
clinical cancer genetic centers, in order to perform genetic stations, specialize in
phenotypic iteration for all the family, which are suspected to present on the basis of family
or background early onset, which are primary derivative of cancer, and we can consider
that each year we have roughly 44,000 genetic stations focused on cancer.
You have here as a distribution of the main and secondary clinical cancer genetics center.
Similarly, as the second floor, we have a national network of molecular geneticist laboratories
for iterative form of cancer, of course for Lynch syndrome, [unintelligible], breast,
and ovarian cancer, but for all over more rare, non [unintelligible] form of cancer.
So we have now 25 laboratories.
For instance, we have in France, 14 laboratories performing bracket one and bracket two analyses.
We have 12 performing correct eye cancer, gene analysis, and the 73 gene are waiting
to be analyzed and corresponding payer [spelled phonetically], both for these cases and relative
to 60,000 genetic analysis.
So, one action, and thanks to the Nichete [spelled phonetically] of the National Institute
and on the side part directed by Professor Fabien Calvo, was, of course, to structure
the next-generation sequencing, both at the germline and also at the somatic level, in
term of the targeted therapy in order to detect on the routine basis all the actionable limitations,
and thanks, there is now a recognition of different platforms, and we have now nine
NGS and bioinformatics in the facilities in order to demonstrate implementation of this
structure through the country to perform exome sequencing, comparative exome sequencing,
between a primary tumor metastasis and germline DNA, and, of course, to perform exome analysis
from germline detection in the context of the strong suspicion of iterative form of
cancer if targeted analyses are negative.
One important mission of this network is also to perform training to bioinformatics analyses,
and with a strong commitment of the clinician in charge of cancer.
So if we are seeing what is clearly meeting in France, in contrast to the marvelous presentation
that we had, for instance in U.K., or was it the Netherlands, are also very powerful,
is we miss, definitely, at the present time, her national platform able to perform very
high-throughput NGS facilities.
So we can consider that we are okay concerning the first step, which is the national network
of laboratories, performing target analysis, and using NGS, not only in the context of
rare disease, but in certain context of rare -- of cancer, both somatic and germline.
We are okay in intermediate platforms, able in complement to the first one to perform
exome analysis, but in contrast to the U.K. organization, we are missing a very powerful
centralized platform able to perform exome and genome analysis with a clinical grade,
in order not only to perform genetic discovery, but also in order to be able to provide molecular
diagnostic.
And we have estimate that what we need per year, if we are considering both what is needed
in terms of rare disease, but also in terms of cancer, is between 10,000 and 50,000 exome
per year.
I'm just restricting my comments of exome, not for genome, considering the challenging
aspect of genetic variation interpretations.
So, one possibility, which is strongly considered at the present time, is that the main challenge
of the Abysin [spelled phonetically] in order to optimize this pipeline in France is, in
fact, to reinforce the National Center of Genomics in every parts, south parts of Paris,
so this National Center of Genomics, which is at the present time equipped with, sorry,
with 3 Hiseq 2005, 14 Hiseq 2000, but only eight are devoted to human genome, one proton,
11 Miseq were able to ensure that within two weeks, roughly raw database of 6,600 gigabase,
correspond roughly to the second European sequencing facility, and one important aspect
is that the National Center is re-equipped with a high performance computing center,
with a total capacity of 120,000 computing goals, but dedicated to genomics we have 3,000
cores, corresponding to five petabytes, and entering exome and whole genome analysis,
and this is coordinated by Jean Francois Deleuze.
So the idea for the future is probably to reinforce this research.
So, to finish my talk, the idea is to complete the pipeline.
So the idea in our strategy first focused on rare disease and cancer is to have these
pipeline organization.
We start first from National Networks of Clinical Centers, both in the fields of rare disease
and cancer, in order to ensure a phenotypic expertise.
Then we are performing [unintelligible] of targeted analysis, thanks to national networks
of medical molecular genetics laboratory.
And after that, at the present time, we are benefiting from national networks of interregional
platforms in order to complete analysis by exome sequencing analysis and training, but
the challenge is the creation of the national plan for performing exome general sequencing
analysis.
The big issue will be, of course, detection and interpretation genetic variation, so that
will be one important aspect of this international platform, which are going train people in
order to ensure a first step of bioinformatics analysis, but the big challenge, half of that
will be transform this variation into a clinical markers, and that will be the work of the
National Network, in order to validate on indefinite samples, and to go back to their
clinician.
And one important aspect, and this will be my last slide, and, of course, if we are here
dealing with genetic medicines, we have a strong implication in France with genomic
research, which is [unintelligible], and we have considered that the top priority, but,
of course, the national development of these exploratory techniques in order to optimize
the detection of disease, the identification of the genetic determinants of disease, and
one important aspect is, of course, development of bioinformatics and biostatistics.
So, I will stop here and be happy to have any questions.
Thank you for your attention.
[applause]
Male Speaker: May I?
Well, my question is how much amount of money was invested to organize these genetic test
centers, including supercomputers and sequencing facilities?
If possible, if you could, separate the sequencing facilities from super computers.
Thierry Frebourg: I will be unable right now to give you an
accurate estimate.
What I can tell you is what was a challenging aspect was how are we going to reimburse all
the genetic tests?
So the way it has been organized was the following: We have convinced the Ministry of Health that
we should organize that as a national lab, so in other terms we have here a map of specialized
molecular genetics laboratories.
Each of them --
Male Speaker: I see, I see, I see.
Thierry Frebourg: -- we are getting some money based on directly
from the Ministry of Health, based on an annual report, right?
Based on those reports, so we are supposed to perform all the analysis for the countries
on a free basis okay?
So, for instance, considering the equipments, so we have different codes corresponding to,
for instance, the last code was roughly 10 millions of Euro in order to have an equipment
of Miseq of medium size platforms, and now if you are considering the main center corresponding
to the center located in Evry, most of the equipment have been based on either private
funding, or national funding, or even European contracts.
Male Speaker: I see.
The computing part is a centralized or distributed?
Thierry Frebourg: Well, there are different scales, so we have
the main power is located in Evry, but as you have understood, since we have five inter-regional
platforms, we have different bioinformatics facilities, and we have -- considering that
even playing with the Miseq, it was really important to have bioinformaticians, so we
have pushed and we succeed to have permanent position for bioinformatics, not only working
in research laboratory, but bioinformatics people working in diagnostic laboratory because
we need quantitative reports, and, as you know, that corresponds to different challenges.
Male Speaker: Thank you very much.
Male Speaker: So, you know, we have 23 clinical genetic
centers in the U.K.
You've got a lot more in your distributions, so -- and we've been thinking that 23 is a
lot, particularly with NGS, but -- so your system must be more fine grained, a smaller
of number of tests per center, or you're doing more tests?
You know, it's -- another problem with having 23 is that they tend to do their own thing
in terms of working out protocols and developing bioinformatics.
Are you controlling your large number of centers so that they use common platforms, or?
Thierry Frebourg: Well, maybe the way I've presented is a little
bit confusing because definitely most of the centers are located in within the University
Hospital for Rare Disease, and we have 26, so you have 23, so it's the same scale.
Male Speaker: Right.
Thierry Frebourg: So, you understand --
Male Speaker: But you had larger numbers for the rare disease
--
Thierry Frebourg: Yes, but because within the University Hospital
we are going to have, for instance, competence centers working on neurological disorders,
but usually, you have local interactions.
Male Speaker: Right.
Thierry Frebourg: So, what you have to consider, at the territory
level, we are dealing mostly with 26 university hospital in which we are -- so it's the same
scale --
Male Speaker: Right.
Thierry Frebourg: --at the clinical level that in the U.K. that
I know a little bit.
Male Speaker: Right, all right, okay.
Make Speaker: Thank you very much.