Telomere Biology and Cancer Risk with Dr. Sharon Savage and NIH Clinical Study Participant

>>I need a hug first. It’s good to see you. It’s been so long.>>I know.>>How are you?>>I’m good.>>Hi, Nancy. It’s good to see you today.>>It’s always good
to see you too.>>And so we’re going to do
your bone marrow aspiration and biopsy to check and see
how your bone marrow is doing. This is part of our
inherited bone marrow failure syndromes study. Doing the bone marrow
today to look for any clonal abnormalities
or changes in the chromosomes in the, in your blood cells because of the underlying bone
marrow failure that we see with dyskeratosis congenita. In the clinical genetics
branch, we study individuals and families at very
high of risk cancer, and several of our
studies are taking place at the NIH Clinical Center
where we see patients and their families, and
their family members, whether they’re affected or not,
for comprehensive evaluations that include things such
as bone marrow aspirations, genetic counseling,
X-rays, MRIs. They see a multitude
of subspecialists because we really want
to know within all of the cancer-prone syndromes
we study, what’s part of having that syndrome, versus,
what’s just part of being a member
of that family? With dyskeratosis
congenita specifically, we have about 100
families and about 130 or 40 affected individuals. About half of those
families have been to the NIH Clinical
Center for evaluation. The inherited bone marrow
failure syndromes study that Blanche Alter opened in 2001 includes the four
major inherited marrow failure syndromes, and dyskeratosis
congenita is one of those. And then it also
includes Fanconi anemia, Diamond-Blackfan anemia,
Shwachman-Diamond syndrome, and some of the other
less common syndromes. Dyskeratosis congenita is an
inherited bone marrow failure syndrome that’s characterized
by increased cancer risk, but it can be very
challenging to diagnose. Patients with DC have a
very wide range of problems that can present at any
age and seem to vary within families and
between families. There are many genes
that, if they’re mutated, can cause DC in our patients. And all of those genes are
related to telomere biology, and it’s telomere biology that we think is causing the
problems with DC patients. Patients with DC have
extremely short telomeres, and telomeres are the
ends of our chromosomes. They are responsible for
keeping our chromosomes stable, but they shorten with
each cell division. And with successive cell
divisions, telomeres get shorter and shorter, and
eventually, cells are, undergo apoptosis, or they die. And so telomere length
is really sort of a marker of biological aging. Patients with DC have
very short telomeres. This was first figured out
in, when the first gene for dyskeratosis congenita
was cloned in 1999, and it’s called dyskerin,
or DKC1. And that, those studies
led to the first findings that telomere length
was abnormally short in the cell lines
from those patients. And then in around 2005 to ’06,
Dr. Alter, within our study, evaluated telomere length in
blood cells of patients with DC of their unaffected
relatives and of patients with other inherited bone marrow
failure syndromes to see if, what the differences were. And what we found was that telomere length was
extremely sensitive and specific for differentiating
patients from DC with, from their healthy
relatives and from patients with inherited marrow
failure syndromes. Patients with DC generally
have telomere lengths less than the first percentile
for age. So that means they’re
extremely short.>>I’ve heard some people say,
like, in DC, in, you know, in a lighter respect,
say, right. Not the serious aspects of
the bone marrow failure, and the fibrosis,
and everything. But to almost an aging disease because of those
shortened telomeres.>>Right.>>Because the telomeres,
you know, they become shorter as you age. They become shorter if you have
a lot of stress in your life. But because we start out
with them so short, in a way, the fact, you know,
I went gray at 13. You know, Charlie [assumed
spelling] had his–>>Yeah.>>Forelock at, you know,
16 or something like that. It almost is, you know,
it’s the cells that need to regenerate more quickly
that are affected, and, or the, or multiply, or whatever. So it’s, it is almost a little
bit of an aging disease.>>It is. You said
that very well. It’s actually exactly right in
that telomeres are much shorter in people with DC than
in people without DC who are at the same age. And it’s the cells that
divide more frequently, like hair follicles, skin
cells, bone marrow cells, other cells like that that need
to be constantly replenished that are at increased
risk for having more–>>Problems.>>More problems–>>Right.>>Because their telomeres
are starting out much shorter than they should be
based on their age.>>Right.>>And that’s exactly
why you have this kind — it’s like a premature
aging syndrome. She said it way better
than I did.>>[laughs] No, I say it–>>See how you say it–>>I say it in terms, when I try
to explain it to my friends–>>Yeah, yeah.>>Because they don’t
understand it at all. And it’s a very difficult
disease to explain.>>Yeah, yeah.>>And because it has
such a myriad of symptoms.>>Well, and that’s what’s
really hard, actually, as a physician and as a
scientist trying to study DC is that there are such differences
in the clinical severity. So there are the patients who
have the Hoyeraal-Hreidarsson, or HH, variant of DC who tend
to present when they’re very, very young as babies
or toddlers. They have cerebellar hypoplasia
— small, a small cerebellum — and immunodeficiencies, plus
problems associated with DC, like the nails and skin changes,
the gastrointestinal changes. And they’re little
children who are, have a lot of medical problems. They, the, another related
variant is Revesz syndrome, which has features of DC, but
also has exudative retinopathy, or some bleeding in
the back of the eye. And then we have patients at
the other end of the spectrum who are older adults who
have a mutation in a gene that has fewer clinical
features or has features that don’t develop until they’re
40, 50, even 60 years of age.>>I mean, really, sort of me.>>Really, sort of you, where–>>You know.>>You know, you, first
symptoms didn’t develop until–>>Early 20s, kind of.>>Twenties.>>Yeah.>>And then classifying,
you know, patients like you who develop symptoms in their
20s versus who develop symptoms in their 40s or even
50s is challenging because it’s this
broad spectrum. And we know now that a big part
of that reason is the genes that are mutated
in those patients, the genes that are abnormal in
those patients, in that people who tend to have the
complications not present themselves until adulthood
tend to have mutations in genes that involved in the telomerase
complex, in TERT, and TERC, and some other related genes,
whereas the more severe patients with the Hoyeraal-Hreidarsson
variance or Revesz syndrome tend to have mutations in DKC1,
in TIN2, in RTEL1, in TPP1. So understanding the genes that cause DC has really
helped us better understand the progression I think
of the disease and the medical complications
we have. When I first started working on
DC in 2005, we had three genes, the, that were known
to cause DC. And our group has
found four new ones. They’re now up to ten,
and we’re still looking.>>Amazing.>>We have, we now know the
gene in about 70% of patients–>>That’s great.>>Which is great, and it’s
helping us understand the biology, but, you know, we
still have to start to apply that understanding
to the clinic.>>And I just want to
interrupt because I, you know, some people think, well, what’s the big deal
of knowing your gene? But for, I, and a lot of
people don’t really understand or appreciate this, but for
somebody, say, like Charlie, who’s not horribly sick, and
who’s young, and who’s of, like, getting close to
maybe getting married if he ever finds a girlfriend,
it is crucial to know your gene because we’ve reached a point
in science and in medicine where he could actually
use preimplantation genetic screening and he can end
the disease in his children. So he can, they can, you know,
do IVF, and they can look for any of the embryos that
carry that gene mutation and discard them, and then only
implant the healthy embryos. And it’s actually been
done in some of the other, you know, several other–>>Some of our patients.>>DC patients already
successfully. But for me to know that Charlie
can have healthy children and not worry — I didn’t
even know I had this disease when I had my children,
so, but he can, you know, not worry about this. And he knows it’s going
to end in our, you know, that he’s the last one that’ll
carry this in his family. So having this ability, but
you have to know your gene. And if you don’t know your
gene, you can’t do this. So the work that you’re doing,
finding these genes, is just, it’s just so important
and so amazing. And I know that there’s still
families that, you know, are just, I’ve had
them say to me, “We’re waiting for
that phone call.” [laughs] You know. And I’m sure you’ll
be making it someday.>>Yes, and we’re working on it. [laughter]>>So–>>Yeah.>>Yeah. But it’s,
it is important. I mean, it doesn’t sound like
it would be, but it’s, you know, not just for that,
but for other reasons. But to me, that’s like
a really important one.>>It is, and it’s
one that patients in our study have used the
information that we’ve gained in this study to then go
on and have children–>>Right.>>Who no longer are at risk
of this disease because–>>Right.>>Of this.>>I mean, we had one that,
you know, they lost one child–>>Yeah.>>To the disease, and then they
wanted to have another child, and they could use
your information to have another child.>>Yeah.>>So it’s incredible.>>So the goals of our
study are really multiple. One is to understand the
clinical complications in DC because we’re really seeing
a much broader spectrum of problems from bone marrow
failure, pulmonary fibrosis. We’ve recently found that pulmonary arteriovenous
malformations are present in DC more commonly
than maybe we thought, cancer in these patients,
and other problems. That’s one part, the clinical
part, which is really important. Another part is the
genetic discovery part in characterizing the genes
that are causing this disease, which brings me to
the third part, which is really an understanding of the biology behind
dyskeratosis, and telomeres, and how that gets
connected to human disease. By knowing why patients get DC, and what effect those
specific genetic changes have on the cells, and how
that affects the telomeres in the cells, which then affects
how well the cells can divide and replicate, will really help
us understand telomere biology. And telomere biology’s
very important in cancer because we know that, as cells
divide, as normal cells divide and telomeres get shorter
and shorter, as telomeres get to a critically short
length, cells are supposed to either stop dividing, which
is called senescence, or die, which is undergoing apoptosis. And so cancer cells continue to divide despite having
critically short telomeres because they increase levels
of an enzyme called telomerase, which extends telomere lengths. And then that allows cancer
cells to continue to divide, which means their
chromosomes aren’t stable, which means they get more
and more changes in the DNA and accumulate more
mutations in the cells, which can then propagate
more cell divisions and the growth of the cancer. So by stepping back and
studying the basic biology of how telomeres work,
we can help under, it’ll help us understand
how telomeres are important in progression to cancer in
the general population as well. And working with families
like Nancy’s families and all of the families in our
study is really invaluable because their contributions
really make it possible for all of those things I said. So they’re generously giving
us their time and energy–>>We get so much
more than you get.>>And their blood. [laughter]>>Yeah, you can
have all you want.>>But we also, the
study, when patients — I should say, actually,
for all of them, whether or not they come here, we help
advise them clinically as much or as little as they want. We send them detailed
questionnaires. We review their medical records. And the other thing that
they give us is their, is they give us blood to study. From that blood, and we make
cell lines, we isolate DNA, and that becomes an
extremely valuable resource for the basic scientists who
are studying why these specific genes affect telomere
biology in the cell. And so I have, gosh,
numerous collaborators who are not clinicians, who
are very basic scientists who just truly appreciate the
fact that we have patients in our study who are allowing us
to create these cell lines to, that then they can study the
function of a specific mutation in a specific gene and how that changes telomere
biology in the cell. Because by understanding that,
my goal is to really take that back to the clinic
and try to fix it.>>I’ve seen lots, and lots, and
lots of doctors, and honestly, even, you know, just, I mean, I had my hips done before
I was diagnosed with it, but then I had them revised
after I was diagnosed with it. And I went in after the
revision, and I said, “I have this disease.” And they’re like, I said,
and they said, “Well, we’ve never heard of it. It doesn’t matter.” I’m like, “It’s a
serious disease. Have a lot of hematological
issues with it.” I said, “I’m going to
need this many platelets, [inaudible] platelets.” I said, “If I need
a transfusion, I’m going to need a leukocyte
depleted, you know, red.” They’re like, “You’ll be fine.” I’m like, “No. Listen to me. I’m not, you need
to listen to me.” And you know what? [phone ringtone]
Oh, that’s Charlie. Sorry. I, but they,
you know what? They just, if you’re, honestly,
when you don’t have a doctor, or, you know, a doctor after
your name, or something, they don’t want to
listen to you. So honestly, you really
need to be as proactive, and challenge them,
and, you know, and when you have a rare disease
like this, it’s difficult. And these are top
doctors in New York City. So it’s nothing like
coming here.>>Yeah.>>I mean, and I’ve had
things that my doctors at home have missed totally. I come down here, they
finally take care of it. Countless times. So it’s, I mean, it’s just
great being able to come here.>>But that’s really I
think the biggest challenge with rare diseases is our
patients are more often than not the ones
educating their doctors.>>Yeah.>>And that’s just
not fair for them. And, you know, so that’s
why we’re here for, to help our patients, and I
think that goes for everyone in the NIH Intramural Program
is that we study rare diseases and we make advances in
them, but we’re also here as a resource for people who
need to learn more about any of these rare diseases that
are being studied here.>>And all the doctors
in your, in the, well, whatever you call it,
the cohort, or whatever, all make themselves available.>>Yeah, yeah.>>I mean, if I have a question,
I feel I can email the doctor and say, what should I
do in this situation? Or, and they all–>>Yeah.>>Say, you know, email
me, or, you know–>>Yeah.>>Don’t feel shy about
asking this question.>>We and others who work in these fields literally
collaborate on writing chapters on every system that
might be involved in each of these disorders. And the information in
these guidelines book, some comes from literature that
is written by others and some from the studies
we’ve done here. And the families
can take these books to their doctors
and work with them.>>And our first product was
the DC Treatment Guidelines, which just came out
at the end of 2015.>>It’s always great
coming here. The doctors are more
knowledgeable than anybody I’ve
encountered anywhere else. Say “dyskeratosis
congenita” to most people and most doctors even, and
they have no idea what you’re talking about. So just the privilege of coming
here is, once a year is great.>>It’s wonderful having
the NIH as a resource, and I think other patients
do the same because–>>Yeah.>>All of you make
yourselves so available, which is unusual
for most doctors. And so you guys have your,
you know, your arms piled high with all your research and
all your clinical visits, but then you’re also there
to be a resource for us. So I don’t know how
you juggle it all.>>[laughs] That’s what
we love doing, though. That’s–>>But it’s, it is
really amazing.>>Yeah. That’s why we’re here.>>And we appreciate it. [laughter] And we
love you for it. [laughter] I just, I would
reiterate exactly what Charlie said, and, you know, I
remember once, they had us, they asked us a question about
how you feel about being here, and I think, you know,
on a basis of one to ten or something, and they asked
us individually, and then the, whoever it was, they
said, I said, “A ten.” She said, “Ten?” I said, “Absolutely.” And I’m like, she’s like, “Most
people don’t say they feel like a ten coming here.” And she says, “Why would
you answer that way?” I said, “Because I feel like
coming here, I’m, you know, I get so much information. The doctors are so amazing. And, you know, it gives me,
you know, as much to take care of myself as possible, as I can
possibly get, and whatever.” And then she said,
“That’s so bizarre. That’s the exact same
answer your son gave.”>>Oh, really?>>And she said, and this, “He
said ten also, and he said, like, almost word for
word the same thing.”>>Wow.>>And she said,
“That’s just so weird.” [laughter] But, I mean,
honestly, we feel really, really, really grateful
that we’re here. And the doctors are
just incredible. [laughs] And they couldn’t be
kinder, and nicer, and, so, and we just really
feel fortunate, so.

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