I'm going to talk about
causes of cancer today. I have nothing to disclose; no conflicts of
interest to disclose. Specifically what I'm
going to talk about, we're going to start off by, again, talking about
what is cancer. I'm going to focus more on a molecular genetic
perspective of what cancer is. We'll differentiate between
sporadic or common forms of cancer versus
inherited cancers, and then I'm going
to talk to you about different types of genes that
prevent and cause cancer. These are called tumor
suppressor genes and oncogene, and I'll go through a
few examples of those. Then we'll talk
about how mutations occur in these genes
that lead to cancer. We'll start off with
think about what cancer is and the different sporadic
versus inherited cancer. First of all, I want
you to think about one word that comes to mind when you hear the word cancer. I see inevitable, which is a very interesting
word to think of for cancer. Scary, growth, worst diagnosis, death, cellular chaos
and aggression, adaptability, scary,
another scary. Clearly, there's a lot
of fear around cancer. Sneaky, that's a
good one; sneaky. Metastasis when cancer
spreads, death sentence. Hopefully you'll
learn that cancer is not always a death sentence. The more we develop
new treatments, hopefully it will become more of a chronic disease in many cases. Certainly it is life changing. That is no doubt. I'll just say from
my perspective when I think about cancer, of course, I think about
everything I'm going to be talking to
you about today. But a common theme of
all cancers is that they arise from uncontrolled
cell proliferation. Cancers arise from uncontrolled cell
proliferation as I said. Our organs and our
tissues normally maintain what we
call homeostasis. Homeostasis means
that the organs and tissues maintain the
same number of cells. They do this by
carefully regulating processes of cell
proliferation and cell death. Another term for
those different ways that cells die and one
way is called apoptosis, which is a programmed
cell death. When the cell intentionally
commit suicide because there's something not right and does not want to spread that. Our cells are carefully
regulated to control the cell proliferation
cell death such that the number of cells
that are born exactly equal the number
of cells that die. We have the exact same
number of cells maintained. Now, what we're looking at
here is a picture of a cell. It happens to be
a fibroblast cell that is looking at it through
fluorescent microscopy. What you see in the green is in the cytoplasm of the cell. There are these micro-tubules basically in the
cytoskeleton of the cell. What's in red here is the DNA
in the nucleus of the cell. Just to orient you there. How does a tissue
maintain homeostasis? Normal cells have
the safe guards to control these processes. There are growth factors,
also called mitogens, and that's because
they induce mitosis, which is part of the
cell division process. These growth factors
promote cell proliferation. Likewise, there are growth suppressors that
block cell proliferation, and they are in careful
balance with each other. Similarly, there are deaths
signals that promote cell death and survival factors
that inhibit cell death. You can see there's all
these safeguards and regulatory mechanisms
that are very carefully balanced to make sure that our cells divide only
when they should divide, and that we have a
careful balance to maintain the exact
appropriate number of cells. Well, what happens when mutations disrupt
these safeguards? We have too much
cell proliferation, then we have the
tumor formation. A tumor forms as a result of a disruption of normal
tissue homeostasis. We have too much
cell proliferation, and little or no cell death. The net result is
too many cells. The important take-home
point from this is that cancer development represents
a progressive destruction, you lose those safeguards
that I've talked about, and you then have
these properties that allow the cell to survive, divide, move to distant
sites which is metastasis, and do all the things that
they shouldn't be doing. When we use the term cancer, we generally mean a particular
type of disease that can affect various organ systems
and tissues of the body. But as you've already learned
from the first session, cancer is truly a collection
of heterogeneous diseases. Theoretically, there can be as many tumor types as
cell types in the body. There are around 200 different
histologic cell types that have been
identified in humans. Theoretically there are 200
different types of cancer. All these types of cancer share some common cell biological
characteristics. At the cellular level, they have some similar
characteristics and they share a similar pathogenesis or mechanism of actually
developing into a cancer cell. But yet, even though they share these common
characteristics, each individual's
cancer is unique. With each and with
molecular technologies, we're finding out just how
different cancers are. No two people have the exact
same version of a disease, whatever that disease is, and that is particularly
true for cancer. An understanding of the
molecular profile of cancer can often provide
information about the prognosis, more exact diagnosis, prognosis,
and treatment options. What all these different
types of cancer, heterogeneous
collection of diseases, what they have in common is that they involve inappropriate
cell proliferation. Cells are dividing
when they shouldn't, and more rapidly
when they shouldn't, and perhaps in different places. They move to different
sites and they're growing in places
where they shouldn't. How do cancer cells acquire the ability to proliferate
when they shouldn't? Well, at the root cause, as I say here, cancer
is a genetic disease. That doesn't mean that
it's all inherited, but cancer is due to
the accumulation of genetic mutations in
genes that are involved in those regulatory safeguard pathways that I talked about, and so they disrupt the
normal tissue homeostasis. Now we know that from early observations that
have been demonstrated, that there is a lag time
between the exposure to a carcinogenic agent
or something that causes cancer and
development of cancer. This was elucidated through
many tragic events, like the atomic bombs in
Hiroshima and Nagasaki in Japan. The radium girls you may have heard about during World War II, they would paint the watch
dials with luminescent paint, and they would lick the tip
of the paintbrush to have very precise paint in the watch dials and many of them developed
head and neck cancers. There are examples with nuclear meltdowns like
Chernobyl and other places. These are all devastating
situations and we learned a lot about cancer
from these incidences. We learned that there
is a lag time between the exposure and the actual
development of cancer. We now know that what
is happening during that the lag time is
the accumulation of additional mutations
that disrupt these normal safeguards and
lead to cancer progression. I'm illustrating that
here in this diagram. These circles represent cells. This this white
circle out here is just a normal healthy cell that then is exposed to a
carcinogen or something that induces some damage
and causes a mutation, disrupts one of those
normal safe guards and allows the cell
to start dividing. Gives it some
proliferative advantage. Well then as this
cell is dividing, it can acquire
additional mutations that give it an
additional advantage. Then some of those
cells might acquire another mutation that knocks out a different safeguard, etc, until you've knocked
out enough of those safeguards in order to grow and to proliferate and
form a full-blown cancer. What this is illustrating
is that the process of cancer development is
multi-step process. What happens during
those steps is that multiple mutations
are accumulating. That is illustrated here as well using an example
of colon cancer. We're looking here at the
interior surface of the colon. You've learned some
of these terms and don't worry about the
terminology too much, but we have a normal epithelium. Epithelial cells are cells that line the surfaces in our body, in the interior of the esophagus and the
stomach and the GI tract, your skin, these are
all epithelial cells. What we're showing
here is that it's a stepwise process
you first have a hyperplasia where
the cell starts to divide more than they should, then they become more
uncontrolled and it develops into a
smaller polyp and then can develop into larger polyps
and become more and more irregular until it develops
into a full-blown cancer. What you can see with
this dark pink part here is that this is
then metastasizing, it's leaving this site
and going to get into the bloodstream and start
to travel to other sites. This is illustrated
that at each of these steps in the cancer
development process, there are additional
mutations that allow the cells to progress into these further along
the cancer pathway. I've talked about how cancer
is a genetic disease, but yet does not mean that
all cancers are inherited. The vast majority of cancers
are what we call sporadic. These are common cancers that result from the accumulation
of mutations in these genes that are involved in these safeguards that a person accumulates over a lifetime. It's a lot of bad luck in a
way of just genetic lack of what mutations you're
acquiring and if someone acquires mutations that
lead to cancer development. There's a complex
interaction between genetic and
environmental factors that lead to cancer development. Common sporadic cancers
are typically developed in an older age in your
60s, 70s, 80s, 90s. Whereas inherited cancers are less common in the
population overall, they account for only about
10 percent of all cancers. However, in the families where they have an
inherited cancer syndrome, the cancers are
very common indeed. These are due to an
inherited susceptibility. There is a particular
germline mutation in a gene that leads to the
cancer susceptibility. What this does, it gives
a tumor a head start. These individuals that have this cancer predisposition
tend to develop cancers at a younger age and
they are at risk for multiple cancers
throughout their life. I'm Illustrating this here. Recall from that
other image where I had the circles where the
cells and the result, a white cell that was a
normal wild-type cell. This is red cells here, are like the red cells
in that diagram that have the first mutation. In this case, for a
familiar inherited cancer, individuals start with one of these mutations in all
the cells of their body. They have a head start
in this pathway, so they keep acquiring
additional mutations, but they've already kind of have a head start in that pathway. Therefore, there's
a higher risk of tumor development and a risk
of multiple tumors again, at a younger age
because you have this head start in the pattern. Now we're going to talk
more specifically about the types of genes that are involved in cancer development. What type of genes are involved
in cancer development? Well, these are genes
that can be divided into two broad categories. We talk about tumor
suppressor genes, which as the name suggests, these are genes who the proteins that they encode inhibit
cell proliferation. They suppress tumor growth. That's their normal function
in the cell in our bodies is to inhibit cell proliferation and prevent tumor formation. The other category of
genes are oncogenes, and these are those that
promote cell proliferation. We need to promote
cell proliferation for wound healing and
many other thing. Certain cells need
to proliferate, we just want them
to proliferate at the appropriate time and only as much as we want them
to and need them to. Again, tumor
suppressor genes are those that inhibit
cell proliferation. Oncogenes are those that
promote cell proliferation. These tumor suppressor
genes and oncogenes act through three
major processes. The first is that
they can play a role in regulating the cell cycles. That means that turning
the cell cycle on, the cell is growing
and dividing into two cells and those cells can divide into further cells, etc. These genes are directly promoting or inhibiting
cell proliferation. The other process is
controlling cell death, and there are genes that promote cell death and genes
that prevent cell death. The third process
that's involved with cancer development
is repairing DNA damage. If damage is not repaired, mutations can
accumulate and that is a bad thing that can lead
to promoting cell cycle, so indirectly affects
cell proliferation. Tumor formation is promoted
by defects in these genes, and we'll talk in more detail about the function
of these genes. I want to give you a
visual example of how these genes affect cell proliferation and
cancer development. I want you to consider the
analogy of a car as a cell. Here's our cute little VW bug, that is our normal cell. Now, normally, we have the gas pedal
and we have brakes, and we need both the gas pedal and brakes to be able to
drive safely down the road. We need to move the gas down to move forward and stop
when we need to stop, speed up when we need
to, and slow down. When our brakes and
our gas pedal are working properly,
we're just fine. Oncogenes are like
the gas pedal. They move us forward when
we need to move forward. Tumor suppressor genes
are like the brakes. So they're stopping. Once again, we have both the brakes
and the gas pedal. When working properly, we're moving forward just fine in a very controlled fashion. But what happens when we
lose the tumor suppressors, so we lose our gas pedal and/or our gas pedal
is stuck down. Sorry, I think I missed said
the wrong thing before. When our brakes are lost or
our gas pedal is stuck down, in either of those
cases, we go, go. The cells are growing and
proliferating uncontrollably. In addition to having our
gas pedal and our brakes, we also need to make sure that our cars are running smoothly. If there is a little oil leak, it might not be a big thing, but if you don't fix it, it's going to be a big thing. That is, there's another type of genes that are involved
in DNA repair, and these are often
called caretaker genes. This are like the mechanic. Mechanics are just making sure that everything's okay with a genome because little problems can turn into big problems. When these genes are mutated, that results in what we call the mutator phenotype because now our DNA repair
systems are not working, so you're accumulating a lot more DNA damage
that's not being repaired and then results
in more mutations. Some of these mutations are
in tumor suppressor genes and oncogene that allow cells to proliferate when
they shouldn't. Let us look at how this
happens in cancer. I'm going to just show you
this diagrammatically. This circled here is a cell and these two blue little lines
here are chromosomes. Our genes are packaged
into our chromosomes here. I'm just showing
you and to remind you we have two
copies of every gene. This is illustrating two copies
of the same chromosomes. For example, of our oncogene, remember, our oncogenes
are like the gas pedal. We actually only need
one of those gas pedals to get stuck down in order
to cause the problem. We have two copies
of the oncogene. If there is a mutation
that activates or turns on one of these copies of that gene when it
shouldn't be on, that's enough to start moving the cell into the tumor
progression pathway. Whereas for tumor
suppressor genes, again, here's the circle of our cell
and the two chromosomes, and we have two copies of
this tumor suppressor gene. Well, with our tumor
suppressor genes, they're like the brakes and we have front brakes
and rear brakes. For the brakes to
go out completely, we need to lose both
the front and the back. Similarly, we need to
lose both copies of a tumor suppressor
gene in order to completely lose the
brakes on the cell cycle, and then that puts us into the
tumor progression pathway. Let me just summarize some of the things that
I've talked about and was a lot coming at you. So to summarize what
we've talked about with tumor suppressor
genes and oncogenes. Tumor suppressor genes
inhibit cell proliferation. They can act directly to
inhibit the cell cycle. There's blocking the cell
from dividing directly, or they can promote cell death. Either case, they are
inhibiting cell proliferation. There were also tumor suppressor
genes that are involved in repairing DNA damage. For tumor suppressor genes, you are inactivating or losing both copies in
the case of cancer, and that leads to unregulated
cell proliferation. For oncogenes, these are genes that promote
cell proliferation, and they can act directly by
promoting the cell cycle. Where the tumor suppressors
are inhibiting it, the oncogenes are promoting it, so they're turning it on directly so the cell
start dividing. Or oncogenes can also
block cell death. That is if cells are not
dying when they should, the net result is
accumulation of cells. In the case for oncogenes, a single copy is
activated in cancer. Again, you will result in unregulated cell
proliferation. A fun little factoid
here, some little trivia, is that we had two very famous
faculty from UCSF that won the 1990s Nobel Prize for discovering the cellular
origin of oncogenes. Before this, there are
many different theories of the cause of cancer from viruses and
many other things. It was thought that it was
something from the outside, more like an infectious agent. What doctors Bishop
and Varmus showed that it actually is
from in the cells that there are normal
genes that become hyperactive that lead to
this overproliferation. This was a very
important finding that really move forward the
field of cancer research. Dr. Bishop actually went on. He also received the National
Medal of Science in 2003, which is very prestigious award. He served as Chancellor here
at UCSF from 1998-2009, and he's still a Professor
Emeritus. He's still around. Dr. Harold Varmus
went on to direct the NIH from 1993-1999. Then he was the Director of the National Cancer
Institute from 2010-2015, he was appointed by
President Obama. We talked about how cancer is a heterogeneous
collection of diseases that's caused by
an accumulation of mutations in tumor suppressor
genes and oncogenes. Although each cancer
is different, we said how they share
certain features. These features we call
the hallmarks of cancer, and that's illustrated here. Don't worry about
all the terminology, I'm just putting this
up here to illustrate these different features that are shared by most cancer cells. The different
hallmarks that allow the cell to grow and
divide when it shouldn't and move to places and live
in distance sites, etc. Actually, these hallmarks of cancer were described by doctors Hanahan and Weinberg and Dr. Doug Hanahan
was here at UCSF. Dr. Hanahan and Weinberg are both very well-respected
researchers and did a lot of pioneering
work in cancer research. Dr. Hanahan was here for
most of that and he's now running an institute
in Switzerland. Now I'm just going to
share with you a couple of examples of tumor suppressor
genes and oncogene. I'll just put a couple
of names to them. The first tumor suppressor
gene I'm going to share with you is called TP53, or you might have heard of P53 as the protein that it encodes. TP53 is often called the guardian of the genome
and that's because it plays a major role in maintaining the
integrity of our genome. Its major role is to respond
to DNA damage and help signal the pathways to
repair that damage. If this gene is
lost or activated, it is a major player in moving forward the tumor
progression pathway. In fact, it is lost
or activated in more than 50 percent of all sporadic common human
tumors and it's probably much higher than that because we're discovering different ways that tumor suppressor
genes can be inactivated. It's likely much
higher than that. TP53 is also involved in cancer predisposition syndrome called Li-Fraumeni syndrome. In this case, there is
a germline mutation of TP53 that is inherited from
one generation to the next. Patients inherit one
copy of this TP53 gene, it's called they have
a pathogenic variant or mutation in that gene, and that gives them a very
strong predisposition to many different cancers. These individuals develop
cancer at a younger age, typically younger than 45. This is very devastating
for these individuals. They are prone to
develop bone cancers, breast cancers, brain tumors, leukemias or blood cancers, cancers of soft
tissue like muscles, and several others as well. They've inherited one copy, but remember tumor
suppressor genes, here we have the front
brakes and the rear brakes. We need to lose both
of them in order to promote tumor progression
to tumor formation. These individuals have
inherited one copy and when one cell loses
a second copy, then that cell can start
to proliferate when it shouldn't and that's why they have this predisposition
to cancer. Another tumor suppressor gene you may have heard of is BRCA1. It's actually two of
them, BRCA1 and BRCA2. These genes are
involved with familial, hereditary breast,
and ovarian cancers. They are also inherited
in a dominant fashion, so it's passed on from one
generation to the next, then you see cancer
in every generation. These genes encode proteins that normally function to repair a very specific type of DNA damage called
double-stranded breaks. If you recall that our
DNA is double-stranded, we have a double-stranded helix, so there's two strands
that are bound together. If there is a break that
goes through both strands, that's the type of damage
that these repair. This is a very dangerous
type of DNA damage. This is a very important
repair system. Mutations in these, again, are responsible for familial
breast and ovarian cancer. Individuals are
typically diagnosed less than 50 years old. These are also mutated in many sporadic breast
and ovarian cancers. Individuals with breast
and ovarian cancers where they don't have a
BRCA1 or BRCA2 mutation, there are other genes that work with BRCA1 and two and the similar pathway that
are often mutated. It's like they have friends
that they all work together, so if any one of
them is disrupted, it can have a similar effect. Now, I also talked
about the mechanic that the DNA repair genes. One type of DNA repair is
called mismatch repair. This repair system
fixes when there are mistakes with the wrong
basis put in when DNA is replicated or
some other process that changes a base so there's a mismatch in that base pairing. This mechanism repairs
that type of damage. When you lose this
repair system, you have an accumulation of these mutations
across the genome. Some of those mutations
will end up being in tumor suppressor
genes or oncogenes and lead to cancer syndromes. In this case, this is
often an early step in the development of
sporadic colon cancers and germline or inherited
mutations in one of these repair genes is
associated with Lynch Syndrome, which is a cancer
predisposition syndrome, mainly colon cancer. These individuals have very
high risk for developing colon cancer as well as uterine, stomach, prostate,
and other cancers. The mean age of
onset is in the 40s, but these individuals with Lynch syndrome can
develop cancers in as early as their 20s
or even in their teens. I also want to
mention an oncogene. Probably the most
important oncogene is ras. Ras gets its name, it was first identified in rats in a rat sarcoma
type of cancer in rats, so it was called ras after
the rat sarcoma virus. There are three different
ras proteins in humans that are expressed in different
tissues and mutation. Remember it's an oncogene, so it's the gas pedal. A mutation in ras, and this gas pedal keeps
it in its active state. It no longer turns off
when it should turn off. It's like your foot
on the gas pedal. If the gas pedal is stuck down, it doesn't matter
whether your foot is there or not, it's stuck down. Once this ras is turned on, it doesn't matter if they're
gross signals telling the cell to divide or
if they're not there, it's still going to
go ahead and divide. Ras is found to be mutated
in about 30 percent of all human tumors. It's found in a
very high percent of certain types of cancers, like pancreatic
cancer is 90 percent. Pancreatic cancers have
a ras mutation and 35-50 percent of
sporadic colon cancers. There are no cancer
predisposition or inherited cancers
associated with inherited ras mutations
because if you would inherit one copy of that
gene, that's all you need. Probably you'd have
tumors forming in utero, basically, it's not
compatible with life. We've talked about
sporadic versus inherited cancers and the different types of genes that cause cancer, tumor suppressor
genes, and oncogenes, and their roles in cell
proliferation and cell death. Now I want to talk
a bit about how cancer causing mutations occur. How do mutations in
these genes occur that lead to
development of cancer? We talked about
the genes, again, that are altered in cancer. How do mutations occur
that lead to cancer? In a nutshell, they result from the
accumulation of DNA damage. Now, our cells are amazingly efficient in
repairing DNA damage. We are bombarded, as we'll
talk about in a moment, with different types of things that cause DNA
damage all the time. Can even think on your GI system and all the things
that were being ingested and everything that's happening in our body and
you be lying everything. It's really remarkable how the vast majority of
that is repaired. But if there is a loss
of a repair mechanism, those genome caretakers,
those mechanics, if we lose one of
those mechanics, then it's a problem. Then we have unrepaired DNA
damage that can accumulate. The more damage
that accumulates, the more likely it is to have mutations in critical genes. Then that leads to what is
called genome instability, that you are starting to acquire
more and more mutations. I'll just comment that the vast majority of our
genome is called non-coding. The actual component
of our genome that is encoded by genes
is only two percent. Ninety eight percent of the
genome is doing other things. It's turns on and off the genes and those
other things that we're still learning what
that all does. But it also can absorb some of the DNA damage without
causing problems. But the more damage
that accumulates, the more likelihood that you'll have damage that
are causing mutations in these cancer-causing genes
and then cancer results. Before I talk further
about DNA damage, I want to briefly orient you to the structure of the
DNA and remind you, the DNA double helix. You probably have all seen
this type of figure before. It's a DNA double
helix wrapped around. What is a DNA double helix? Well, there's actually
the two strands, as I mentioned before,
the two stranded helix. You can see this blue part here is a sugar
phosphate backbone, and then what comes off of
that backbone are these bases. These bases are adenine
and thymine or T, adenine A, thymine T, Guanine G, and Cytosine C, and they pair together
in a very specific way. A pairs with T and T with A, and G pairs with C and C with G. That's the only
way that they pair. When we have a
sequence of a gene, what we're reading is A, T, G, A, C, etc., just reading those bases
along the strand of DNA. How does DNA damage occur? It can occur spontaneously
or just randomly, both within ourselves and
from our environment. There are alterations that
can happen to our DNA bases. There are when a DNA replicates, different errors can occur. Again, most of the time
these are repaired. There are by products of
normal cellular metabolism like free oxygen radicals that can cause oxidative damage. Again, most of the
time it's repaired, but sometimes it slips through. There are environmental causes; UV light, cigarette smoke, there are chemicals
in cigarette smoke, other toxic chemicals
in our environment, things that we ingest, etc, that can damage
or alter our DNA. As an example of the
spontaneous damage that can happen towards DNA just
within ourselves every day. Here's our DNA
double helix here, and showing a
little more detail, showing right here
is a base pair. There's one partner on the
other strand over there, and here's one base. I'm blowing that up
here to show you. This is that sugar phosphate backward
bone I talked about, and this is the base. This is a cytosine and this
is an amino group here. It's not that important, but just to show
you what can happen is just spontaneously
in our cells, this cytosine can
become what's called deaminated or lose
this amino group. Well then it's not
an cytosine anymore, it becomes a.. Uracil is
not normally in our DNA. Uracil is in RNA, but not normally in our DNA. This is going to make a
change in the DNA sequence. This is something that is
deamination or changing a cytosine tour uracil is actually quite a
common occurrence, occurs to a 100 bases
per cell per day. This is something
that's happening to all of us all the time. Again, this is
typically repaired by a particular type
of repair system. To just show you how if it's
not repaired, what happens. What I'm showing you here, these gold lines here are the backbone of the DNA
and here are the bases. Normally we would
have a G and a C. But when that C is deaminated
and it changes to a U, well U does not pair with G, and then when this
strand is replicated, you end up putting in
an A that can pair with the U and then the next
round of replication, this U is going to be changed
to the partner of A in DNA, which is a T. What happens after two
rounds of replication, instead of having a GC, you end up having an AT. That is a big change
to the sequence The take-home message
is that if there is an altered base and
it's not repaired, it leads to a mutation that's
maintained in the DNA. Now normally, this right here is a mismatch that
would be repaired by a mismatch repair mechanism
that specifically looks for these types of mismatches or this mismatch, I
should say right here. That looks for this little bulge that there's a mismatch
and repairs that. From our environment there
are many different types of mutagens or things
that cause mutations. One example is in
cigarette smoke. There is a chemical
that's called benzo(a)pyrene that's
in tobacco smoke, that forms an adduct on our DNA. It basically distorts the
structure of the DNA, and that causes major
problem when the DNA is trying to replicate. Another type of damage
is from UV light, and that also causes a
structural damage to DNA. I told you how the
bases pair from one strand to the other
in a very particular way. Well, what UV light does is cause bases to pair
within the same strand. Instead of paring
to their partners in the complimentary
strand they're binding to each other
in the same strand that forms a kink in the DNA. Which again is a major problem when you try to
replicate through that. There are different types of DNA repair systems that
repair specific damage. Here we have our mechanic,
there are different mechanics. They each have their own
very specialized roles. For example, I talked about
the mismatch when there was a U put in instead of
the C, for example. Don't worry about the
different types here. I just want to let you
know that there are different types of
DNA repair systems and they work very efficiently to maintain
the integrity of a genome. But considering that we have three billion cells in our body and every
time they're dividing, it's pretty remarkable that we actually don't all have
cancer at a very young age. We really do have
efficient repair systems. But of course, as someone said early on,
when you think of cancer, you think inevitable, Some people will say,
well, if you live long enough, you'll
develop cancer. But our DNA repair systems, I do want to give a shout
out to them because they do work amazingly well. These again are caretaker genes. What happens when we
lose our caretakers? That is when we accumulate
more DNA damage, as I've said before, and I just wanted to illustrate this for you in this graph. If we're looking at what
this graph is showing on the x-axis is the number of mutations and the y-axis
here is the time. We're just thinking about
as cells are dividing, that there's a low
background rate of mutations in our genome, and most of them don't cause
us any problems at all. If there's loss of
DNA repair system, then all of a sudden you have a whole lot of
mutations that occur, and that's when the cell is
called genetically unstable, which is a characteristic
of advanced tumor cells. In fact, the mutation rate
in cancer cells is typically 10-20 times higher than
it is in a normal cell. Again cancer cells acquire many mutations once
you lose DNA repair. Coming back to this figure
that I showed earlier, if you recall this
multi-step process of the tumor
progression pathway, as has been mapped
to colon cancer. What I'm showing you here, there's all the steps
and we talked about how different mutations occur
in different safeguards. We now know that there are
these tumor suppressor genes and oncogenes along the way. Once you lose DNA repair, and this is thought to
be an early step in the process of colon
cancer development, once you lose that and you
increase genome instability, then we start to accumulate all these other mutations that then lead to a full
blown carcinoma. I want to summarize what
I've talked about this far. I've talked about from
the beginning how cancer results from genetic
mutations that disrupt these normal tissue
homeostasis so disrupts the processes that control
the normal number of cells and tumors arise during this multi-step process of accumulation of
multiple mutations. The mutations are
in genes that are involved in cell
proliferation, cell death, and DNA repair and it
is the inactivation or loss of tumor suppressor
genes and the activation so the inactivation or loss of the brakes on the cell cycle and the activation of oncogenes are sticking down the gas pedal that causes the problem and
leads to tumor formation. Cancers, although they are a heterogeneous
group of diseases, they all share certain
hallmark features. We talked about how random
DNA damage is constantly occurring due to normal cellular processes
and environmental factors. Most DNA damage is repaired by specific
reinforcement mechanisms, but unrepaired damage leads to mutations that are
maintained in our genome. If you lose a DNA
repair mechanism, that leads to the
accumulation of a lot more mutations and
that leads to what's called genomic instability and the potential to acquire
many more mutations, including those in
critical cancer genes. Genome instability is believed
to be an early event in tumor progression that allows for the acquisition of all
these other mutations. I know I went through a lot of information in a
short period of time, so I'll be very happy to
address your questions. But first I wanted to segue two sessions later
in the course. Why is all of this important? Why is it important
to understand the molecular basis of cancer? Well, it's important to have a more accurate diagnosis and prognosis of the disease
and we will talk about diagnosis next week, as well it gives us
the information. This is a huge area
of research and clinically applied research is developing targeted
cancer therapies. Once we know this
particular gene is turned on when it
shouldn't be turned on, well, maybe there's a way
that we can target that to block it in the cancer
cells specifically. This is a big area of research, is developing targeted
cancer therapies. This leads to more precise and individualized
cancer treatment, as you will learn much more
about later in the course. With that, I thank you very much and I will look forward
to taking your questions. That was excellent,
doctor Hyland. Thank you so much
for that overview. Kathy, I'm going to send
this first question to you. The questions states, how does CRISPR technology
factor into cancer prevention, particularly in people who
are particularly susceptible, such as those who have
Li-Fraumeni syndrome. Great questions. CRISPR technology
or gene editing has huge potential.
We're not there yet. As we know, there's
some successes. We're really hopeful
that this may be a way of helping in
the future to correct when somebody has an inherited cancer
predisposition that's very specific mutation to be able to correct that mutation. We're not there yet. But hopefully the
technology will be able to be used
in cases like that. As we're waiting for more
questions to come through, I have a somewhat simpler
question as someone who has a PhD in this specifically, how do you look at the world
and how do you consider protecting yourself from
DNA damage in the world? It's a great question.
Well, I certainly wear my sun, as you can tell, I need it. I'm very high-risk. Just being aware of
things like that. But of course, you
don't want to walk around, live your life, being worried about everything, but I think just being aware. I am someone that eats
very healthfully, I'm very aware of
what I ingest and eat very natural foods and try to avoid processed foods
and things like that. Somebody asked in the Q&A about blood based assays to
detect cancer early. I just wanted to address that
and say a couple of things. First of all, we'll cover on blood based assays in the
final session of the course. You'll learn more about that. But I do want to
connect that concept of a blood based assays
to Dr. Hylands talk. For those who haven't
heard of these, when we think about molecular
testing for cancer, we traditionally have done that testing on the tumor itself. Someone will get a
biopsy as you'll learn more about next
week and then there are various tests we can
do on that biopsy on that tissue specimen to learn about the molecular
features of the cancer. Blood based assays
are a pretty cool, fairly recent development where you can draw somebody's blood just through a
standard blood draw and there are elements of
the cancer that can be detected sometimes through that blood test because tumors, cancers in the body sometimes shed things
into the bloodstream. You'll learn much more about that in our final
session of the course. But often the things
we're looking for on these molecular tests and including those
blood based assays, are some of the same
genetic mutations that Dr. Highland was talking about earlier that are pretty specific to
different cancers. Through looking for some of those mutations through
a simple blood draw, we now sometimes have the
ability to figure out that somebody has cancer and even what type of cancer it is, and even what
treatments might be helpful for somebody
with that cancer. These blood draw assays, these tests have
come a long way. The person who asked
the question was asking about detecting cancer early. Right now, we're using these
blood based test primarily to examine features of cancer in someone who we already
know has cancer. It hasn't quite hit
primetime yet to use these blood based
assays to detect cancer early in a reliable way. But the research is
really promising. I have a feeling
that we'll be doing that in the
not-too-distant future. There are already some companies working actively on this. Just wanted to
address that question and I'll toss it back
to you, Dr. Arora. Thanks, Dr. Brondfield. Dr. Hyland, one of the
questions was in the chat, so I'll just ask that one. Is there any study on how not processed food or
nutrition affects cancer? Meaning if one consumes a heavy amount of
unprocessed food, does it affect cancer growth? I think that's what they're
asking in the question. I don't know about the studies. I'm not up on the current
literature on that, so I don't want to
misspeak about anything. But in general, there are studies about nutrition and
lower risk for cancers. I don't know if either Dr. Brondfield or Arora know anything more
specifically about that, but I do know that just having a healthy diet
with fresh vegetables and whole grains
and all that are shown to reduce risks of
certain types of cancer. Do you know anything
more specifically? I'm happy to
comment. There's not strong data out
there to strongly recommend a particular
diet or against other diet to prevent
or treat cancer. We do, as Dr. Hyland said, generally recommend a
healthy diet for people with cancer and to just minimize the chance of cancer
over someone's lifetime. There are suggestions
though that diet may be linked to certain
types of cancer, for example, the prevalence of gastric cancer and
colorectal cancer. Both gastrointestinal
cancers are different in different parts of the world and the theory is that someone's diet in
different parts of the world may have
something to do with that. But again, in terms of
general recommendations, we just recommend a
generally healthy diet. Diet does not seem to be a
very strong contributor to cancer risk for
particular cancer types as compared to
other risk factors. Making just an important
part of that too is that if one were to be
diagnosed with cancer, diet doesn't seem
to change at all, the growth patterns
of that cancer, once it has already
developed in the body. But I agreed that the
suggestion is the strongest with things that are
originated in the GI tract. Dr. Hyland, I'll go to
this question next. I think it's a question we
probably all wonder about. What's the timeframe
between DNA damage and mutations and full-blown cancer or the diagnosis of a cancer? He can't really say one
timeframe specifically. It's going to depend on what the mutations
are that occur. They've just shown for people that were exposed to radiation
or somebody like that. There was a decade, seemed like a couple of decades. But for people that
had large exposures, that will be a shorter timeframe than then you would just naturally acquire
mutations over your whole life, where someone might develop
a cancer in their 70s, someone that had an exposure
might develop cancer just two decades after that exposure, or
something like that. But as far as just the
typical DNA damage that we're exposed to, it's really just an
accumulation over a lifetime and it depends
on the type of cancer. Certain cancers are
more dependent, and to that point,
too many details, are more dependent
on certain oncogenes or tumor suppressor genes
that play more of a role. If those happen to be mutated, then that cancer might develop
faster in someone else. If those mutations don't happen, then it's a slower progression. I know it's a very loose
way of explaining that, but it's very dependent
on the type of cancer and the
mutations involved. Thanks. I'm going to toss this question
to Dr. Brondfield. Does Oncotype DX test
score test only oncogene for breast cancer
and prostate cancer? That's a great question. I have learned some about the Oncotype DX score mainly in the setting of breast
and prostate cancer. I am not aware of it being
used for other cancer types, but that may just be the
limits of my knowledge. I'm not entirely sure but just to make sure others know what we're talking about. Oncotype DX is a gene
panel that is used in breast cancer primarily to look for common mutations
in breast cancer. It can tell us something about how aggressive we expect
the disease to be, its responsiveness
to chemotherapy. It's another example
of a test that can be done on a cancer to help identify some molecular
characteristics about it that really impact
diagnosis and treatment. Thanks, Dr. Brondfield.
Dr. Hyland, I'm going to ask
you, did you want to comment on something? I see another question
that's related to that. If you don't mind if I can jump forward one
question to this, what I'm seeing the Q&A. Is the molecular profile
of all patient tumors now routinely evaluated prior
to treatment decisions, or is this done only for certain types of
cancer like breast cancers? I would just want to jump in with that
question because it relates to what Sam was
just talking about. Sam, you can say
more about this. But here at UCSF, there is the UCSF
500 Tumor Panel which is not on everybody. But it's often done on people, not just breast cancer, on many different types of cancer to give
information to see, are there certain genes
that are mutated, certain oncogenes, for example, that if they are mutated, it might indicate that
a certain type of targeted therapy could
work for that patient. Sam, do you want to say
anything more about that? I think I would just echo
what Dr. Hyland said, that clinically we're using broad molecular testing panels all the time in cancer now, I would say in most cases, especially if advanced cancer. We are sending these
broad molecular panels. You will learn more about
these molecular panels in our next week's session about
how we diagnose cancers, so much more to come there. But yes, we're using
it quite a lot. While I'm unmuted, I will also address a comment
that I saw in the chat. In response to comments
about diet and cancer, someone brought up a
really important point about what's the relationship
between obesity, diabetes, and cancer. I'll just answer that
by saying that diabetes for sure is important
in relation to cancer. Diabetes is a known risk
factor for pancreatic cancer. Yes, in general,
maintaining good health, avoiding obesity and
reducing body mass index, and reducing one's risk for diabetes will also reduce
one's risk for cancer. That is an important link and one reason why we generally
recommend a healthy diet. Thanks. I'm going to
ask this one next and then I'll go to
the other question because it was on the
chat a little earlier. I'll leave it open to
either of you to answer, but there are several
types of breast cancer. I've heard that a
testicular cancer can be closer to one of those breast cancers than two types of breast cancer.
How does that work? That comes down to the
molecular profiling. We're going to have Dr.
Brondfield add to this as well. But there can be certain
mutations that occur and this is where cancers are
more grouped by their molecular
profiles sometimes. Apologies. There's
another dog barking across the hall and my dog
is totally triggered now, so sorry about that. If different types of cancer have a more similar
molecular profile, they actually may
act more similar than another cancer of
that same cell type. So breast cancers might be
more different molecularly. What was the example? I forgot if that was a prostate
cancer or something else. If they have more of the
similar molecular profile, meaning similar
oncogene is turned on, similar tumor suppressor
genes turned off, they'll respond to more
similar treatment plans. Dr. Brondfield, do you want
to say more about that? Sure. That was a great answer. I'll just add that, currently when we talk about
different types of cancers, as you've heard, we
usually refer to them by the organ that
they originated in, so breast cancer,
testicular cancer. But as Dr. Hyland described and as you'll
learn more about next week. In fact, a cancer that
originates in the breast, for example, can look
very many different ways. It can be one of a number of
sub-types of breast cancer. There are other
soft tissue cancers that can start in the breast. There's a whole
variety of types of cancer that can start
in a particular organ. I'm not aware of one that looks particularly like
testicular cancer. But testicular cancers or as cancer is very
similar to them, can start outside of the testicle and
other organs as well. I think the theme
here is that yes, we name different
cancers by the part of body that they start in. But there's all sorts of different sub-types within that, and you'll learn much more
about that next week. I liked this question. There's one really good crystal ball question that
I thought I would leave towards the end of our
Q&A session if that's okay. But this next question, I'll ask Dr. Hyland
to answer this. If a mutation occurs, does it change all of
the DNA in one's body? That's a great question. The answer is no. So it depends on, mutation may occur
in just one cell. There might be different
mutations in different cells. But unless that mutation
is in a germ cell, so in the egg or the sperm
that has been inherited, produces offspring
in next-generation. In that case, it is maintained
and then it would be inherited in the child's
DNA in all of their cells. But if a mutation
occurs in you and just one of your organs cells, it is not everywhere, it's just in that cell. Thanks. I think that's a
really important concept to take home because we
get so many questions from people asking, does this mean that I
have a genetic mutation that are my kids going
to be affected by this. It's really rare for those
types of mutations to cause. That's a small subset
of cancers overall for the types that are once
mutations that you're born with. Another question,
while cancer has been around for a
very long time, what do you attribute
the increase in cases to in the last century? I think it would be great for
an answer from both of you. Well, one thing that
comes to mind is that people are living longer. The longer we live, the more likely it is
that will develop cancer. So that's one part of it. Actually, Dr. Brondfield, I wanted see how you're
going to respond to this, because there's certainly
different things in our environment and different things that
we're exposed to and whether there are truly more carcinogens
that we're exposed to then in preview
than a century ago, is a good question or
whether it's really has more to do with that our
population is aging. Yeah. As the audience might remember from Dr.
Arora's talk last week, the trajectories of
different cancer types are pretty variable, and in fact, lung
cancer is going down. That's probably because people were in general smoking less. But why are some cancers going up or why have they gone up
or spiked in recent years? You may also remember
Dr. Arora showed a graph of prostate cancer, and that one went up
really suddenly years ago. The biggest reason
behind that is more testing for
prostate cancer. Not necessarily that the number of times it's happening in
the population is going up, but that we're just
finding it more often. The answer, I think
overall is pretty complicated and depends
on the cancer type. But I think it's multifactorial. Some cancers are
increasing, for example, colorectal cancer that
may have to do with diet. Some are going down, lung
cancer like we talked about, and some we're
detecting more often because of better
testing technology. So a complicated question
and a really good one. All right, I leave the
crystal ball question. Now thanks everyone for
your great questions. We still have time,
so feel free to add some more
questions to the Q&A. But I think this question
would be great for both of us, for Dr. Hyland and for Dr.
Brondfield to answer today. If you had a crystal ball, where do you see
cancer diagnosis and treatment to the next 5, 10, 15 years? Which cancer, if any, could be a 100 percent
curable in the future? Dr. Brondfield, are you looking
into your crystal ball? Yeah. That is a
fantastic question, and there's a couple of
questions in there I think. It looks like the first one is, where do we see
cancer diagnosis and treatment in the next
5, 10, 15 years? The second one is, can any cancer be 100 percent
curable in the future? My thoughts on that, just taking a piece at a time. Diagnosis in the next 5, 10, 15 years, as you'll learn about both next week and in the
final session of the course, there are multiple
new innovations in the diagnosis of cancer
that have happened recently and are
continuing to happen. A couple of the big
innovations are better imaging
techniques that take advantage of certain
molecular features of cancer. We're just getting better
and better at detecting even very tiny deposits of
cancer in the body by imaging. That should continue
to improve over time. Molecular diagnosis, as we
were talking about earlier, not only through
biopsies of cancer, but also from relatively
straightforward blood tests. The more you can detect and the more information you get
from a simple blood test, the easier things go in general, because it's a relatively
non-invasive test to do. Probably more advances in that. I do think we're
going to start to see early detection of cancer
through blood testing, which we talked
about a bit earlier, but it has not reached
prime-time yet. I think that will come in
the not-so-distant future. Treatment in the next
5, 10, 15 years. Treatment is just constantly evolving and we'll talk a lot more about that in
two weeks from now. You'll also hear probably about some advances in treatment in the final session
of the course too. I might leave that just for those sessions because
it's a big question. But to summarize
there's a lot of cool advances in treatment
that are ongoing. Then the last part of the
question, which cancer, if any, could be a 100 percent
curable in the future? It's always hard in
medicine to talk about a 100 percent or things
that are certain. There are some cancers that
we consider highly curable now and will probably become even more early
curable in the future. A good example is
testicular cancer, one of the most highly
curable cancers out there. But it's still not 100 percent. I don't know that we'll reach 100 percent curability for a particular cancer type
anytime in the near future. But I think we're just going up and up and up and getting
better and better. I think that's the best
answer I can give for that. Any other thought
to say Dr. Hyland? Going to ask what about some
leukemias and lymphomas, and with some of the new
therapies for those, they're pretty done successful. Dr. Arora, perfect
to answer that one. Yeah. That's absolutely what
I was thinking about too. Dr. Hyland in our Leukemia
and Lymphoma world we have made huge advances
in the last few years, especially with
immunotherapy for cancers that previously had
been completely refractory to our
standard therapies and even things we
had on clinical trial suddenly are curable
after someone has unfortunately relapsed on
five lines of treatment. Now we can cure them with CAR T or by specific
T-cell engages. Leukemia it's totally
changed the game, and leukemia and
lymphoma and in myeloma, there's been several new. You'll hear about this
as well in, I believe, one of our last sessions specifically about
immunotherapy, really exciting hot topic and a really cool drug
that's being used. Initially started to be
used in the hematology or the blood-based cancers
or liquid cancers, but is also being used as well in solid organ
malignancies, and we have a lot of
clinical trials at UCSF. That stuff is exciting. I know that you're going
to have a whole session on cancer treatments and
the new breakthrough, so you'll learn a
lot more about that, but I think this is an area
that is just so exciting with immunotherapies coming out
and more targeted therapies. When we talk about
targeted therapies, just to clarify what
we mean a little bit more that typical
chemotherapies, we're just hitting
any dividing cell, which is why people would
have a lot of nausea, a lot of diarrhea, it hits
GI tract and lose your hair and all the other side effects because it was just hitting
every dividing cell. Targeted therapies are those
that are trying to target just the cancer cells versus
the non-cancer cells. The more we understand the molecular profiles of
different types of cancer, and then figuring out, and not just the
molecular profile, but understanding the
biology underneath and why targeting one molecule will work versus targeting
another molecule won't, developing better-targeted
therapies, I think, is really going to help in
the next decade, I'd say. Thanks, Hyland. I think we have a few
additional questions, I missed one and the chats, I'll ask this to Dr. Brondfield. Does staging mean
stage 4 means death is imminent compared to when someone gets diagnosed
with stage 1 cancer? Great question, and
we throw around this term stage or
staging all the time. You will learn more about that next week in our
diagnosis session, but just to answer that, stage 1 to stage 4 does not describe how close somebody
is to the end of their life, it instead describes how advanced their cancer
is in the body. For example, in general, a stage 1 cancer is a single tumor in one
part of the body, often that can be surgically removed and potentially cured, whereas stage 4 generally
means metastatic or spread beyond where the
tumor started, in fact, usually to distant
sites in the body that are pretty far from where
the cancer started, and that is most of the time
not a curable scenario. The stage really
matters in terms of what the next steps
in treatment are, but it doesn't describe how close someone is to
the end of their life, it just describes how advanced the disease is within the body, and you'll learn more
about that next week. Thanks, and I'll
toss this question, I think, to Dr. Hyland, and feel free to ask
Dr. Brondfield as well, but maybe both could answer, but what cancers can start from the breast other
than breast cancer? Dr. Brondfield, I'll have
you chime in as well, but I believe from
my understanding the cancer starts from the
organ that it starts in. To flip your question around
a bit of cancer that's a breast cancer can move to a distant site and can
be someplace else, but would still be
breast cancer cells. Now, what other cancers
can start from the breast? Only breast cancer can
start from the breast. But if breast cancer cell
move to someplace else, so you have a metastasis in the bone or a metastasis
someplace else, it's actually
breast cancer cells placed in that other area. But to my understanding, you can only have breast
cancer start from the breast, is that correct, Dr. Brondfield? Thanks, Kathy. I'll just add one thing
which is that I agree that most of the time when a
tumor starts in the breast, that it is one of the more typical types of
breast cancer that we see. There are unusual scenarios, some more common than others, where we're really surprised by a biopsy result from a
tumor in the breast. A couple of examples. One is certain types of soft tissue cancers called sarcomas can start
in the breast. There's one called
a phyllodes tumor. That one when we get that
result out of a breast tumor, it totally changes the
approach to how we would treat that cancer that
started in the breast. We don't usually even call that breast cancer
because the type is so different from the typical
breast cancers that we see. Another example is that rarely lymphomas can start
in the breast as well, and those are examples of
blood cancers that Dr. Arora treats that can start
in many places in the body, but occasionally in the breast. I think the take-home
message there is we may do some imaging and find a cancer or what looks like
a cancer in the breast, and most of the time
that's going to be a typical type of breast cancer, but sometimes there's some really rare
types that can start in the breast that surprise us and are treated
quite differently. Those are great examples,
Dr. Brondfield. We have a fresh question
in the Q&A that I think I will pass
it to Dr. Brondfield. How is a distant recurrence differentiated clinically
from a second primary? I think it's a great question. It is a great question. Excellent question. I'm not sure I'll answer that
in other sessions, so I'm glad you asked. What we're referring
to here is that let's say that someone has cancer
and the cancer gets treated, and then they don't have any more cancer in the
body to our knowledge, but then down the road, a cancer appears again, and the question in that
scenario is always, is this a new totally
different cancer or is this a part of that first cancer that maybe
the treatment didn't get 100 percent of it
and now it's coming back in, say a different site. The way we distinguish those scenarios is through
a biopsy typically. We want to actually get
a piece of that tumor, and again, you'll learn
about biopsies next week, but we want to get a piece
of the tumor and examine it under the microscope
and potentially do some of the molecular testing that Dr. Hyland was alluding to earlier around some of
these genetic mutations, and through that testing, we can usually pretty
accurately identify, is this a totally
new cancer or is this that same one
that's just coming back? If I can piggyback on your answer to just connect
with something that I said earlier when
I was talking about how white people who have familial cancers are at
risk for multiple tumors, they're actually at risk for
multiple primary tumors, to use the terminology, because all the cells
of their body have the initial mutation that pre-exposes every cell towards
the tumor progression. You can have different cells
acquire different mutations and develop into
multiple primary tumors. You can both have metastasis
and primary tumor, but when we say that people with inherited
cancer syndromes are at risk for multiple tumors
and multiple primary tumors, and different types of cancer. Someone might have
uterine cancer and colon cancer or
something like that. Thanks, Dr. Hyland. We
have another question which I think is all been
such great questions, I would like to ask Dr.
Hyland to answer this. Can cancer treatments
such as chemotherapy or radiation increase
the chance for developing other
cancers down the line, and maybe add to
that question, why? That's a great
question, and again, I'm going to ask Dr.
Brondfield to follow up. This has been a challenge with treating childhood
tumors, in particular, using radiation for childhood tumors and
a concern whether there'll be cancers
later in life. There is some risks
with radiation. I think that radiation
treatments have gotten much better
and very focused. There is less risk of that than in decades ago when radiation was just given in larger
doses and broader areas. I don't believe
that chemotherapy really will cause
cancers in the future, but I'd like to hear what
Dr. Brondfield says. Again, I think where
we're moving now is towards very
targeted treatments, both with radiation being
physically more targeted, and targeted therapies that have less and less risk for future
cancers. Dr. Brondfield. Thanks, Kathy. I will correct
one thing and say that chemotherapy definitely
is linked with secondary cancers down
the road as is radiation. The way that this
happens is that both of those types of
treatment can impact and cause mutations
in DNA just like the ones that Dr. Hyland
was referring to earlier. Typically, cancers that
result from prior treatment, from chemotherapy or radiation
take many years to happen, usually something like
a decade or longer. There are some types of
chemotherapy that can cause cancer sooner than that. When that happens, it's usually a leukemia and can happen from certain types of
chemotherapy within a couple of years of
getting prior treatment, but these secondary cancers
down the road are rare, they're not common events after chemotherapy or radiation, but they are really important
things to know about in any one who has received any radiation or chemotherapy. Great. Well, I thank
you, everyone, for the great questions, I'm so glad that we were
able to talk back and forth after Dr. Hyland's
excellent presentation. I learned a lot from our
presentation, Dr. Hyland, and your slides were
just really beautiful, so look forward to learning from them for
years to come as well. Thanks everybody and thanks
Dr. Hyland for coming. Thank you, it's a pleasure.