Ins and Outs of NETs – Know Your Genetics
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Ins and Outs of NETs – Know Your Genetics

I’m gonna start this talk with a
genetics lesson because some people may be very savvy in genetics and some
people may know nothing about genetics so we’re gonna start at an introduction
to genetics and then we’ll talk about the genetics of the person what I mean
by that is the inherited genetics that you’re born with and we’ll end with the
genetics of the tumor which is what happens in the tumor itself so for
talking about our genetics lesson we’re gonna start talking about personalized
and precision medicine it’s what got me to go to school to be a doctor and that
physician scientists we’re all unique we all have individual thumb prints that
makes us different and we all have individual DNA now our DNA as humans is
actually very similar it’s what makes us humans but my DNA has slight differences
from your DNA and your DNA it’s what makes us all unique individuals and it
was really in the 1990s when people thought we could really harness the DNA
for a personalized medicine and that’s when the human genome project really
started and the idea was instead of treating everyone with the same disease
the same way we’re gonna look at this particular person’s DNA and be able to
treat them or predict risk of disease for that individual and I remember this
day some people remember when the man landed on the moon
I remember in February 2001 when the nature and science journal came out with
the completed human genome project I was a graduate student in the middle of my
MD ph.d program and this was awesome so the idea again once we could sequence a
person’s DNA then we can take everybody and instead of giving everyone the same
treatment where we know it won’t work for a large percentage of people we can
instead look at the DNA or look at characteristics of a person and give the
right treatment to the right person at the right time and it’s the idea that
we’re evolving from a one-size-fits-all system to a system of predictive
preventive and precision haier takes a lot of people to do all
this it takes bioinformaticians mathematicians technicians computer
scientists biologists medicine doctors nurses genetic counselors and it takes
ethicists how does it take ephesus anyone remember the movie Gattaca the
mid-1990s i loved these actors so that was my movie but the real reason i bring
it up is because it talked about the ethical side of knowing everybody’s
genome and knowing your DNA sequence it this movie it was Hollywood but it said
you’re already predestined based on your DNA to get this disease that disease
marry this person have this job and that’s kind of a scary thought and so
actually in 2008 there was a law that came out and it’s called the genetic
information non-discrimination Act or the Gina law and this law protects
individuals so that health insurance and employers cannot discriminate against
anyone for having a certain genetic condition and this is a really important
law to to have in place when we’re dealing with genetic predisposition to
cancer syndromes so there are a lot of pros and cons for personalized medicine
I’m not going to go through all of them but the Pro is that we really think it
can transform health care so that we can really give the right person the
treatment and predict and prevent disease some of the cons is that it does
cost a lot of money to do DNA sequencing and DNA testing and there’s those public
policy issues which I talked about as well but the ultimate goals really are
to provide personalized medicine to prevent and treat complex diseases like
neuroendocrine tumors provide knowledge of disease risk and individualized drug
therapy okay we’re gonna take a step back we’re just gonna say what is DNA
some people really know this but some people probably heard it once maybe in
school and that’s it so let’s start there
DNA is our genetic code determining the characteristics of every living thing
DNA looks like a twisted ladder and I I love this picture but I’m kind of a
DNA dork the rungs of the ladder are made from four types of blocks that we
call bases and the bases are abbreviated by letters ATC and G there’s about three
billion of these base pairs in our DNA in our human genome and the sequence of
which these bases occur they matter because that labels the instructions for
how our bodies are going to function and so we can understand DNA this is an
example of a section of DNA sequence it’s a lot of ATC’s and G’s but in fact
we break them into three-letter words or codons and these three-letter words go
together they string along to make a sentence and you can think about the
sentence as the gene so the gene is broken up of these DNA base pairs into
three little words going along so a gene is the part of the DNA that tells our
cell how to make a specific protein it does that by making a message first and
that message is RNA and that RNA then gets translated into the protein and the
protein is the building block of our body and we have tens of thousands of
proteins to make our body function but in order to have the proteins that our
body needs to function it’s all based on our DNA sequence so now we’re going to
talk about variations in DNA we mentioned that we’ve all have very
similar DNA it’s what makes us humans but we all have slight variations in our
DNA so when we talk about variations in our DNA the way I think about it is that
the vast majority of them have little impact on our health because it just
makes us all different brown hair curly hair straight hair etc I think of it as
the American versus British way of spelling a word theatre with an ER
versus re labor with the U without the U the meaning of that word is the same but
it’s a slight variation that we all have on the other hand we can have variations
in our DNA that actually change the meaning and if it changes the meaning it
causes a damaged protein that’s not going to work properly and so in
example here is state if you change this T to an L you have slate or if you add
an S in front of the word eat it becomes seat very different meaning of those
words but a single letter variation so the benign variant where it’s just the
American versus British spelling is called a benign variant when it changes
the meaning of the word it’s called a pathogenic variant or mutation we’re now
trying to use the words pathogenic variant but we’ll use them
interchangeably mutation pathogenic variant does that make sense so far okay
alright so now we’re gonna talk about inherited pathogenic variants versus the
pathogenic variants in the tumor itself so when we talk about inherited
mutations or pathogenic variants we call those germline you’re born with this
change in your DNA it’s in every single cell in your body and we can test for
that usually by a blood test because again the change is in every cell of
your body including your blood cells so this is the test that leads to us
figuring out if there’s a predisposition for developing cancer and we’re going to
talk about some of the net’ predisposition syndromes when we talk
about tumor mutations we call that somatic mutations what that just means
is the DNA change was not there when you were born but it happened by chance in a
single cell in your body and then that cell grows and pull if rates and becomes
a tumor and we test for that only in the tumor because it’s not in the rest of
your body it’s specific to the tumor DNA change and we sometimes want to know
what DNA changes are in the tumor because it might help us find a
treatment that will be specific for your tumor okay so let’s talk about the
inherited genetics related to neuroendocrine tumors will start with
pancreatic neuroendocrine tumors about 10 to 15% of pNETs are associated with
genetic syndromes and those syndromes are here and we’ll talk about them in a
minute but again 10 to 15 percent that means 85
to 90% of people with pancreatic neuroendocrine tumors don’t have an
inherited genetic cause it just is sporadic it happened by chance okay
but 10 to 15% there might be an inherited reason for having these tumors
for lung nets and for small intestine Nets they’re rarely associated with
genetic syndromes they’re almost always just sporadic as far as science knows
right now but if they do happen with a genetic syndrome it’s often associated
with multiple endocrine neoplasia type 1 and we’ll talk about that in a minute
now to me the reason that caring for carcinoid change to the NETRF is
because we want to encompass all neuroendocrine tumors not just GI tract
typical or bronchial lung carcinoid and that includes some other neuroendocrine
tumors I’m not going to talk about all of them because they’re neuroendocrine
tumors in the skin in the breast and the prostate they’re everywhere but I’m
going to talk about the most common in addition to the pNETs, lung NETs and GI
NETs and one of those is pheochromocytoma paraganglioma
these are neuroendocrine tumors of the adrenal medulla and the extra adrenal
ganglia respectively and different than the GI Nets a very high percentage 35 to
40 percent are associated with hereditary syndromes in fact it’s the
most common solid cancer to be associated with an inherited cause okay
lastly I’m just gonna mention medullary thyroid cancer
it’s a neuroendocrine tumor in the thyroid I mention it because you’ll see
when we talk about the syndromes that some of the syndromes patients can get
neuroendocrine tumors here it’s about 25% of all medullary thyroid cancers
that are associated with a hereditary cause and that’s multiple endocrine
neoplasia type 2 and we’ll talk about that in a minute as well so let’s review
all these syndromes I just threw at you we’ll start with multiple endocrine
neoplasia type one and that’s because it’s the most common genetic syndrome
that’s going to be associated with the pancreatic neuroendocrine
tumors it’s actually pretty rare in and of itself about 2.5 people per hundred
thousand have men1 and it’s called multiple endocrine neoplasia type one
because there are multiple endocrine glands with neoplasia or tumors and it’s
really noted for the 3 p’s these patients who are have multiple endocrine
neoplasia type 1 have a germline inherited mutation in the men1 gene and
they’re at risk not saying they will get but they are at risk to get pituitary
adenomas x’ the pituitary gland sits at the base of the brain they’re at risk
for parathyroid hyperplasia and adenoma x’ that causes high calcium kidney
stones and some other problems and 30 to 70 percent it’s a wide number because it
varies depending on the study will get pancreatic neuroendocrine tumors and
they’re often multiple pancreatic neuroendocrine tumors in the pancreas
patients with MEN1 also are at risk for many other neuroendocrine tumors GI
neuroendocrine tumors they can get adrenal tumors very commonly but they’re
rarely the neuro endocrine type type they get feos less than 1% but they can
get neuroendocrine tumors in the thymus as well as the lung the next syndrome
that’s associated with neuro endocrine tumors we’re going to talk about is von
hippel-lindau disease this is caused by a mutation in the von hippel-lindau gene
it occurs in about one in 36,000 individuals so a little more common than
MEN1 and patients with VHL they also are not destined to get every single one of
these but they’re at risk for lots of different cancers and tumor types kidney
cancer hemangioblastoma is which are tumors in the nervous system endo
lymphatic sac tumors which are in the inner ear and then about 17 percent of
patients with VHL will get pancreatic neuroendocrine tumors again often
multiple sites in the pancreas and they’re also at risk for
pheochromocytomas the adrenal neuroendocrine tumor about 20% of
patients will get feos and they’re often bilateral in both adrenal glands
the neck syndrome is neurofibromatosis type 1 actually did my PhD work in this
disease studying the neurofibromas which are benign peripheral nerve tumors not
neuroendocrine tumors but this is caused by mutations in the NF1 gene kurzon one
in 3,500 individuals these are the characteristics that define NF1 but it
turns out that although it’s not part of the clinical criteria patients who have
this genetic syndrome are also at risk for neuroendocrine tumors specifically
pheochromocytomas it really ranges it used to be thought only one percent of
patients with nf1 got feos but now we think that it’s much more common
probably closer to 13 percent it’s just no one was looking for them before and
then very rarely there’s also an association with pancreatic
neuroendocrine tumors with this syndrome as well okay we’re moving on I know I’m
throwing a lot we’re gonna tie it all back together afterwards multiple
endocrine neoplasia type 2 so this is similar to multiple endocrine neoplasia
type 1 just in the sense that they get lots of tumors in lots of different
endocrine glands but with men2 it’s caused by a different gene it’s the
mutations in the RET gene occur in 1 in 40,000 people and patients here get
almost everyone gets medullary thyroid cancer again neuroendocrine tumor of the
thyroid glands and about 50% will get the pheochromocytomas but there’s no
risk that we know of of the pancreatic neuroendocrine tumors or GI
neuroendocrine tumors being associated here lastly I’m going to spend a minute
on the hereditary pheochromocytoma paraganglioma paragangliomas
pheochromocytoma syndrome either way the this syndrome is caused by mutations in
actually five different genes but they’re all part of the same complex
they’re called the SDH complex or succinate dehydrogenase complex it
controls energy in our cells and it turns out that the risk of developing
Pheo para varies and it’s not that I for some of these so there’s a lot of
people walking around with mutations in these genes who never develop disease
but if certain percentage do sdhd D for dad because this gene and AF2 are
paternally inherited so if you inherit this gene from your mom you won’t get
disease but you’re still at risk to pass it on to children but if you inherit
from your dad you’re at risk for Pheo para and all of these genes are
associated also with kidney cancers GI stromal tumors perhaps pituitary tumors
some mention of pancreatic neuroendocrine tumors with sdhd but very
very low risk there there’s a bunch of other genes for Pheo para had to throw
it in because it is my net I’m not going to talk about these because they’re
really rare but just to know Pheo para has many many many inherited genes
associated with its risk so I just talked to you about all these syndromes
so you might be saying oh my gosh should I be tested for any of these syndromes
and it really depends so I told you that pancreatic neuroendocrine tumors they’re
only inherited up to 15% of the time so we don’t recommend that everybody with a
peanut be checked for one of these heritable conditions but if you have
multiple pancreatic neuroendocrine tumors or you have another feature of
one of these syndromes then you should have genetic testing to see if you have
an inherited cause of these four lung nets and small intestine nets they’re
very rarely inherited so again we don’t recommend testing everyone who has that
type of net unless you have other features of these syndromes for Pheo
para and medullary thyroid cancer it’s a bit different because the inherited
rates are much much higher so every patient with a Pheo para and every
patient with medullary thyroid cancer should have germline inherited genetic
testing to see if they have a heritable cause so why do we care we care because
if you know you have an inherited cause it’s gonna help your doctor screen me
for recurrence for another primary neuroendocrine tumor and for those other
features of all these syndromes that I talked about so it’s important to know
if you do have an inherited reason for your net developing and also if you with
the net have an inherited cause we want to test your blood relatives because if
they don’t have the gene they’re not at increased risk for developing this type
of cancer if they do have that gene change then they may be at risk and we
can screen them so we catch things early nets as we mentioned earlier takes a
long time to get the right diagnosis but if we know there’s an inherited
predisposition an inherited possibility we can screen people early and catch
things early so the question I get asked a lot is but if I know I have this is it
mean that I’m automatically gonna get a neuroendocrine tumor or that I’m going
to get another one of the tumors in each of these syndromes and the answer is no
I tried to point out that percentage of people with each of those syndromes and
for some it’s high but some it’s not that high so it doesn’t mean because you
have a gene that you’re automatically going to get disease just means you’re
at increased risk to potentially get disease and one of the research things
that I do is try to understand everyone who has the gene mutation how do we
predict who’s going to get disease and who isn’t can we find genetic reasons
why some people are protected and never get disease even when they have this
gene because maybe that could be a therapy to give to people who do have
disease alright I’m going to spend the last couple minutes just talking about
the tumor genetics this is different than the inherited genetics so remember
this is the DNA change that’s not in your whole body it’s just in the tumor
itself and we can utilize that perhaps to understand better treatment options
for that tumor so it’s interesting because across all these different net
types I talk to you about there’s actually some similarities in the
mutations that form in the tumor earlier we heard about a TRX and Dax it’s in
pancreatic neuroendocrine rumors and our research found them in
pheochromocytoma and paraganglioma stew so there’s overlap with these mutations
that occur in the tumors and that might help us better understand why
neuroendocrine tumors form and why sometimes they can metastasize and it
might be that there’s possible drug targets so you might have had a surgery
or a biopsy where your oncologists or surgeon sends that tumor tissue off to
have genetic testing foundation medicine for example is one of those companies
there are others and that’s to look at what DNA changes happened in your tumor
not your whole body just your tumor because maybe by chance there’s a
mutation in there that we have a specific drug target to and that we can
treat you and your tumor with a specific drug based on the mutations now
neuroendocrine tumors they’re often pretty indolent which is a good thing
that’s why I can live for so long with them that also means that the tumor
itself doesn’t always have very many mutations in it again a good thing
because it’s not very aggressive usually but it makes it harder sometimes to
identify these special targeted therapies when there’s not a lot of
mutations in there but again maybe not a bad thing okay
so personalized medicine again taking that tumor DNA and instead of giving
everyone the same treatment find out based on the tumor DNA which treatment
is best for which patient the right treatment right dose right patient right
time for the right outcome so two slides on the future where I see we could go
for nets specifically we already kind of used targeted treatments and therapies
so PRT luda Thera and MIB AZEDRA for
pheochromocytomas and paragangliomas these are specific targeted therapies to
specific receptors in the tumors so we have to make sure the tumor takes up
these molecules and that’s why we do the gallium dotatate scan or an MIB G scan
and if the tumor takes up those molecules we can treat with this type of
treatment but now I could go even farther and maybe the future will let us
know what genetic markers will help us determine if you’re
gonna respond so just because the tumour takes it up a lot of people respond but
some don’t and maybe we could figure that out based on the genetic markers in
the tumor another future direction is using the person’s DNA so now I’m going
back to your germline DNA I already told you if we know you have a germline
inherited mutation in all the cells in your body we’re gonna screen you a
certain way to look for tumors and try to catch them early but maybe and this
is a lot of my research we can do use that DNA to figure out to prevent to
predict who’s going to get disease and prevent it from occurring so this could
be the future of some of the genetics fournette tumors so hopefully I haven’t
scared you away talking about all the genetics we covered that DNA variants
can be benign or pathogenic we talked about that there’s many genetics
syndromes that predispose to neuroendocrine tumors but that not
everyone who has a net is gonna have a genetic syndrome and I should say not
everyone with the genetic syndrome DNA change is going to get a net and that
hopefully tumor DNA mutations are going to provide more and more information
about therapies and how to treat specifically each individual person so
thank you very much for your time and I look forward to your questions at the
question answer session

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