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Sukhdev Sinha: Very good morning, and I especially thank
the organizers for giving us the opportunity of this presentation. First off, I'll make
the presentation. And earlier we had given the feedback of, I should say, to Rita [spelled
phonetically] that what India requires and what are the grey areas and green areas. So,
yeah, so I'll be quite brief in my presentation.
So this is basically the structure of my presentation, these are the ideas I'll be covering. And
so, first of all, I'll be speaking about the strategy that has benefits and targets in
the Indian context.
So our focus is on trans-disciplinary participation, education, and knowledge base, coordination
and preparing --
Male Speaker: Why don't we just move --
Sukhdev Sinha: Sure, yeah --
Male Speaker: Yeah, that's better.
Sukhdev Sinha: Thank you. Preparing the regulatory guidelines
and creating the infrastructure in the genomic area -- genomic medicine area.
Now, actually, here actually I highlight the areas likely to be benefitted: the diseases,
the predictions, how it is going to benefit, and the diagnostics. And how increased knowledge
is going to benefit us.
Now here, actually, before I mark on the slide, actually, I would like to mention that from
India there are four major [unintelligible] agencies. One is the department of biotechnology,
from where I belong, and another is department of science and technology, another is department
of health research, which comes under ministry of health and family welfar, and another is
[unintelligible] scientific and industrial research that is again under [unintelligible]
ministry.
So, in this particular slide I mention about the DBT institutions, and particularly here
I would like to highlight the NIBMG and BMGC in the Eastern part of our country. Actually,
this institution was established by the department. It has about a $50 million budget for the
initial period of five years, and it has a clinical attachment called biomedical genomic
center and a clinical [unintelligible] in Calcutta. So, NIBMD is located in Kehalani
[spelled phonetically], and its clinical wing is in Calcutta, so both are functional at
this point of time. And in the subsequent presentation, Partha will address what is
going in NIBMD, so therefore I am not elaborating on this.
And here I'd like to mention in the top of area the RCB, that is Regional Center for
Biotechnology, yesterday I did mention that is uniscal [spelled phonetically] category
two center which has focus on education, learning, and research. And there is also an institution
called Translational Health Science and Technology Institute, and also, you can see NBRC, that
is National Brands Research Center. So, there's a cluster there, and also the National Institute
of Immunology.
So they're all engaged in biomedical area, and recently we have embarked on a inter-institutional
program on pre-term birth, so -- because India's burden is quite heavy, it's almost annually
3.5 million, and there are other institutions down south and also western part of our country
that is National Center for Cell Science and National Institute of Animal Biotechnology,
Center for DNA Fingerprinting and Diagnostics and inStem. And the lowest one down more south
is -- that is, RGCB, Rajiv Gandhi Centre for Biotechnology.
Now, in genetic cataloging of ethnic groups, these are the important areas actually: data
coordination, which will include the clinical data, molecular involvement of molecular geneticists,
and anthropologists. So, creation of baseline data on various ethnic groups for disease
susceptibility is very important, therefore, we consider, and what -- actually, our emphasis
is on promoting translational research, and that is towards diagnostic kits, then vaccine
development using reverse genetics, then molecular tool for surveillance, and these are some
of the examples of what we have been doing.
Now, in the prenatal care area, we - - this is also our focus, and here, actually, on
the third one we have mentioned initiating that is what I mentioned on preterm birth,
and we have genetic clinics at different clinical set-ups for screening -- doing the prenatal
diagnosis.
Now in cancer genomics and epigenomics of -- in genomics and epigenomics of cancer,
then transcriptomics of cancer, and NIBMG is a part of International Cancer Genomic
Consortium, and India's part is oral cancer, which Rosa [spelled phonetically] Partha will
be highlighting.
Now other areas, these are the areas which we want to highlight, and here, actually,
we are interested in harmonization with international ethical guidelines. We have a national bioethics
committee, and their department is the nodal agency.
Now what are the hurdles? Now, these are the hurdles: handling large dataset, evidence
for health treatments are based on research goals, research waste due lack of expertise,
lack of regulatory guidelines, incidental findings majorly, and lack of knowledge in
primary healthcare providers. So, we need better technologies, large dataset for patients,
and lack of translational or interpretation. And last not the least the funding and political
will.
Now, what are the possible collaborative areas? So, one count [spelled phonetically], streamlining
guidelines for implementation and pre-clinical and clinical trials; this is number one. Number
two is use of traditional knowledge and integration into modern genetics. Next one is cloudsourcing
for translation of genetic data. Next is development of new methods of disease classification based
on recently discovered genetic principles. Next one is building community interest and
participation. Next is building data sharing capabilities; unify strategies ongoing various
places; and set up biobank facilities; and training of manpower; and building study cohorts.
That's all, I want to stop at this stage.
Now I'll invite Professor Majumder to deliver his talk and together we can address the questions.
Thank you.
[applause]
Partha Majumder: All right, thank you. So you got an overview
of what's going on in India in various areas of human genetics, genomic medicine. I just
want to add a few sentences to what Mr. Sinha just spoke, which is that in terms of the
past, India did not participate in major international collaborative efforts, but more recently,
in 2009, India did decide to participate in the International Cancer Genome Consortium.
So what I'm going to talk to you about is primarily what we've been doing in the International
Cancer Genome Consortium, so it's probably going to be a little bit more scientific than
policy or general discussions.
I also wish to mention that there are other agencies aside from the Department of Biotechnology,
such as the Counsel for Scientific and Industrial Research, who also partner internationally,
and right now the CSIR, the Council for Scientific and Industrial Research, they have a major
partnership with the Mayo Clinic. Again, in areas impending on human health and genetics.
So, we -- in India, because there are multiple agencies that fund research, it's a little
difficult to find all of the information in one place, but all that I'm trying to point
out is that aside from Department of Biotechnology, which was a major focus of Mr. Sinha's talk,
there are other agencies; he did mention some of them: the India Council of Medical Research
collaborates primarily with the World Health Organization, and let me start with what the
Indian Council of Medical Research has done over a 20-year period, which actually is the
background of India's participation in the international cancer genome project.
So the Cancer Atlas of India, which is primarily an epidemiological atlas, was created for
a period spanning two decades, and this was done in collaboration with the WHO. What this
has accomplished is a nationwide epidemiological database, and this goes to -- not to the village,
but a cluster of villages that's called a district for every single district of India,
and what I will try and show you are those graphs that pertain to oral cavity because
I'm soon going to sort of specialize in the oral cavity.
So this is -- these data sets are done by the ICD codes, ICD-10 codes. So this is cancer
of the tongue, and as you can see that, these are adjusted incident rates for 100,000 population.
and as you can see that, these data are primarily done for every single district of India, clusters
of villages. There are certain areas that could not be covered because of political
disturbance and other kinds of stuff, but by and large, it's nearly complete. So we
have -- this is cancer of the mouth, this is cancer of the tonsil, and in particular
I would like to draw your attention to geographical differences even within India. So, for example,
cancer of the tonsil has very high incidence and prevalence in the northeastern region
of India. This cancer of the oral pharynx; again, fairly high. Nasopharyngeal carcinoma
cancer is fairly high in the northeastern region of India.
The institutions that are primarily involved in cancer research, to add to what Mr. Sinha
just said, there are other institutions that are outside of the department of biotechnology
who are into clinical and basic research, basic biology of cancers, a number of institutions,
and then there are adjunct, like technology platform facilities, such as the Center for
-- whatever, I can't remember the acronym but --
[laughter]
-- molecular platform center for advanced molecular platforms or something it is called.
Then there is the Institute for Bioinformatics in Bangalore and C-DAC in Pune, Center for
Advanced Computing. Then, the focus of research is primarily -- are several in terms of foci.
Some are based on disease burden, so, for example, oral and head and neck cancer about
which I'm going to talk to you about. Cervical cancer has a major focus in India, primarily
because its high prevalence. Breast cancer is catching up; in some areas breast cancer
is even more prevalent that cervical cancer, and so there is a lot of work that is going
on in terms of -- with respect to breast cancer.
As I said, the northeastern region in India there is a very high presence of nasopharyngeal
carcinoma. Gallbladder cancer, which is almost nonexistent in most places of the world, except
that along the major river, the river Ganges in India, in the Amazon basin and in the Nile
valley you do find a lot of gallbladder cancer, and so this -- a unique feature of gallbladder
cancer in India -- well, not so unique, but by and large it's focused in various geographical
locations of the world, India being one, and so there is some research that is going on
in gallbladder cancer. Gastric cancer, some of the tribal populations from one of the
northeastern states called Nagaland has a very high prevalence of tribal gastric cancer,
and probably this is related to diet or the microbiome, so some would -- that's emanating
there. This is a difficult region to collect data from, but still some institutions are
taking major leads in collecting information on collecting gastric cancer from there.
Again, the gliomas has the center -- the Council for Scientific and Industrial Research has
a major funding as a major focus on the gliomas, so the Department of Biotechnology usually
does not fund glioma research because it's funded by the CSIR.
All right, so I will spend the next few minutes primarily on the International Cancer Genome
Consortium and India is participating with oral cancer of a specific variety called gingivobuccal
oral cancer, and I'll tell you in a moment why we are specifically talking about gingivobuccal
oral cancer. The entire project is funded by the department of biotechnology, which
is under the Ministry of Science and Technology in India. Squamous cell carcinoma of the oral
cavity is the eighth most common cancer; about 250,000 new cases arise annually. Two thirds
of them are in developing countries, causes about 125,000 deaths annually. It accounts
for about a third of all tobacco-related cancers in India. The site distribution of oral cancer
is very interesting. In the West, predominately what one finds in terms of the cancer of the
oral complex is that it's predominately tongues cancer in the West, and it's -- and the gingivobuccal
complex is about a quarter. In India, three-quarters is gingivobuccal complex and only one-quarter
is tongue. So there is a huge difference in site presentation of oral cancer.
The hazardous combination of course is tobacco, areca nut, which is a very highly psychoactive
substance, calcium hydroxide on the specific leaf called the betel leaf which is widely
used. So what we did was to select patients with oral cancer and do exome sequencing on
the blood DNA and on the tumor DNA, and I obviously don't have the time to describe
to you in detail, but these are the genes that we found were significantly mutated.
Some of them are known, known pairs; some of these genes are not known -- or at least
until we published our study or conducted our study, these genes are not know to be
associated with head and neck cancer, and we found them to be associated with head and
neck cancer, and we -- actually, the discovery sample size was 50, and we validated these
results in 60 patients, and these are the genes that are significantly mutated. The
pathways that are most significantly mutated are, of course, p53, apoptosis pathway, viral
carcinogenesis; about 20 percent of our oral cancer patients also had HPV infection, but
-- so we looked at the data on those patients that had HPV infection, but we didn't find
anything fascinating or anything that's deviant from the rest of the oral cancer patients,
so there was no specific association with HPV.
Neurotrophin signaling pathway is a new pathway that seems to be altered in gingivobuccal
oral cancer and when signaling pathway. I'm going to skip this slide; it's a slightly
busy slide. So, essentially, these are the genes that are significantly regularly mutated
in oral cancer. These are the genes where we found copy number variations, and this
is the mutational profile. So you have some patients with very small number of mutations
and some with very high number of mutations, and these are the sequence contexts in which
the SNVs occur, and if one looks at this closely, we do find tobacco signatures in terms of
the sequence context where SNVs or these alterations -- single-nucleotide alterations take place.
The copy number variations, those are the genes that are recurrently -- found to have
recurrent copy number variations. In GSTT1 is completely deleted in several of our oral
cancer patients, and the ones that are partially deleted -- genes that are partially deleted
are these genes. We obtained evidence of whole genome duplication in seven tumor samples.
If you look at patients and look at profile these patients are -- clustered these patients
based on their mutational profiles, essentially what we find is that one cluster contains
that comprises CAPS8 and FAT1 mutations; the second cluster, the bigger cluster, comprises
p53 mutations; and the third cluster contains a variety of genes that are mutated. If you
look at disease-free survival, what you see if that there are differences in disease-free
survival in these molecular subgroups. If you -- if one looks at patients, one of those
subgroups has patients with mutations in MLL4, although the sample size is small, but when
we do the Kaplan-Meier, we find that individuals who have the mutation survive longer, have
disease-free survival of 20 months, while the ones without mutation have disease-free
survival of 13 months. So there is a seven-month gaining of age when the MLL4 gene is mutated.
The article has just been published in Nature communications.
And the one last point that I want to make with India's participation in the International
Cancer Genome Consortium is that we have not only contributed to the effort, the international
effort, but I and my colleagues in the institute, and in the Tata Memorial Hospital, which is
the clinical site for -- clinical collaborative site, we've gained a lot by participating
in this international consortium because we have been able to exchange protocols, we have
been able to exchange methodologies, and share data and resources. So it's been wonderful
participating in this consortium, and I do believe that when genomic medicine consortia
are coalesced through the efforts of NHGRI and other international partners, India will
participate and will stand to gain. Thank you very much.
Geoffrey Ginsburg: Maybe we have time for one question, which
I will ask. So, as you know, one of the focal points of what we're trying to do here is
also -- is on the implementation side, and I didn't see, but maybe it exists, the linkage
of the extensive cancer genome -- cancer sample cancer genome database to anything that looks
like an electronic medical record where you can, you know, know about medication, about
treatments, about outcomes, and correlations potentially that would be useful for understanding
genetic backgrounds to correlate with response. Can you comment on that?
Partha Majumder: So, in India, one of the biggest problems
is that the largest patient pool is in the government hospitals. That's where the vast
majority of the patients in respect to [spelled phonetically] disease come in, and that's
where electronic medical record keeping is pitiful. So it's only in the private sector
that there is some [unintelligible] of electronic medical records, but in the government hospitals,
virtually none. The government is waking up to understanding the importance of electronic
medical recordkeeping, but it's really non-existent.
Geoffrey Ginsburg: So just to be clear, this research that you're
talking about is all in the government hospitals, not in the private hospitals?
Partha Majumder: Which one?
Geoffrey Ginsburg: Well, the --
Partha Majumder: This one?
Geoffrey Ginsburg: The cancer -- the broad based cancer genomics
program that you have --
Partha Majumder: These are essentially -- so most of them are
actually private hospitals, and that's where the data are coming from because of the quality
of the data.
Geoffrey Ginsburg: Thank you.