Hello, thank you for joining us today. My
name is Josie Kagey, and I'm a cancer
genetic counselor here at UCLA. I work
with families to help personalize
screening recommendations for cancer. I
work with community members who have
been affected and unaffected with cancer
in the genetic counseling clinic. If you
have any questions, please submit them
online, and we'll be able to answer them
after the talk is over. So, most people
are surprised to learn when we sit down
for genetic counseling that most cancer
is not hereditary. So, you can see from
our chart here that most cancer is due
to a sporadic cause. About 20% of cancer
is considered familial cancer, and 10% of
cancer is a hereditary cancer, and I'm
going to show you what that means. So,
this is an example of a family history
of a sporadic cancer. So, this is how we
take a family history in a genetic
counseling session. You can see this
individual has been diagnosed with
colorectal cancer at age 65, you can see
that she is a woman
due to the circle--men are squares--so we
have dad's side of the family over here
and mom's side of the family over here.
In sporadic cancer, we know that as we go
out into the world, we are exposed to
carcinogens every day, the water that we
drink, the air that we breathe, and so our
cells are constantly being insulted, and
cancer can start to develop. So this is
what we typically see in the general
population. This is an example of a
familial pedigree, or a family tree, that
we make, so there is a clustering of
colorectal cancer in this family. The
ages of diagnosis are pretty typical for
colorectal cancer. We know that in
familial cancer, there is a combination
of things going on because families
share their environment, and they also
share their genetics.
So, these factors all come together
to cause cancers. Genetic testing is
often not helpful for these families
because we can't nail down one specific
factor, but rather it's a combination of
things that is causing the cancer. So,
this is an example of a family tree of
hereditary cancer, so you can see this
person with the arrow, that's what we
call our proband. So we designate the
patient that we are speaking with--this
is a woman who is diagnosed with
colorectal cancer at age 42--
you can see that there is colon, ovarian,
prostate cancer in the family, and so we
take a thorough family history--sometimes
we ask for pathology reports, sometimes
we ask for death records--to find out the
diagnosis in the family.
This person was diagnosed with colon
cancer at age 42, which is younger than
we would expect to see colon cancer.
There are multiple generations affected
with cancer, and in hereditary cancer, we
can see individuals with multiple
primary tumors, so maybe they had
colorectal cancer twice, or colorectal
cancer in melanoma, so we ask about all
of the different tumor types when we're
in a genetic counseling session. Another
thing that we ask about is we ask--we
don't mind--the patients often tell me,
you know, my family member had cancer, but
they didn't die of it. So, it doesn't
matter if they died of the cancer or not,
it's that that tissue became cancerous.
So why are we doing this? The goal is
classification for this family. So if you
have a sporadic form of cancer, then you
and your family members are going to
follow standard screening
recommendations. If you have a familial
type of cancer, this is when we can start
personalizing the screening
recommendations. So if you have a
first-degree relative with colorectal
cancer, you should start colorectal
cancer screening at age forty or ten
years earlier than the earliest diagnosis of
colorectal cancer in the family. If you
have a hereditary form of colorectal
cancer, we are going to look at this
specific gene that caused your
colorectal cancer, and we are going to
make recommendations based on the tumors
that are involved with that gene and
what the cancer risk is associated with
that gene. So this is what I sit down and
talk to patients about--we break this
down to the cellular level--so inside
each one of the million cells that
creates us, we carry our DNA, so if you go
to Ikea and you pick up an instruction
booklet for furniture, that's exactly
what the DNA is in our body--it is the
instruction booklet for how our body is
going to be built. So these genes write
the instructions for proteins, and
proteins are really what do the work in
our body. So the genes that I'm talking
about are called tumor suppressor genes,
and some of them are listed here in this
column. These genes are supposed to
prevent you from developing cancer, so
you can understand that if we have a
mutation or a misspelling in one of
these genes, that you are not as well
protected from growing cancer, and you're
going to be born with an inherited risk
to develop cancer. So this slide is meant
to show you a few things. These are some
of the syndromes that have been
associated with hereditary colorectal
cancer, and you can see, for example, Lynch
syndrome has been associated with
multiple genes, and if you have a
mutation in one of these genes, there is
a possibility for multiple types of
tumors, and so that's when we can
personalize screening recommendation
based on the syndrome and based on the
gene. These are some of the syndromes
that have been associated with the
polyposis syndromes. So, polyposis is when
you can have many polyps in the colon.
These polyps can turn into cancer, but if
we remove the polyp before that, that's
when we have a success. So, some of the genes
associated with the polyposis syndromes
are listed here. You will notice that
these genes can cause quite a few polyps,
and there are different inheritance
patterns with these particular genes, so
that's why it's important to sit down
with a genetics professional that can
walk you through how this was inherited
through the family. So, this is an example
of one of those inheritance patterns. The
typical inheritance pattern that we see
with hereditary cancers--autosomal
dominant inheritance. So, while giving you
an example, here is a father who has a
gene mutation. We'll say he has Lynch
syndrome. So, the way that these genes
work is that we have two copies of each
gene because we got one from mom and one
from dad. So if this individual has a
mutation, there's one copy of the gene
that works just fine protecting him from
cancer and there's one copy with the
mutation, so there is a 50% chance, or a
one in two, that he will pass that
mutation along to his children. It's
important to keep in mind, say, those
children started to be tested--each one
of their tests is independent from the
next sibling. So, I've had families where
all of the children inherited the
mutation, or maybe just one of the
children inherited the mutation--it's a
coin flip, 50-50, each time. So, this gives
you a picture of how cancer develops in
the body. This is a person who is not
born with an inherited risk for cancer,
they were not born with any genetic
mutations, but over their lifetime, as
their cells copy the DNA to make new
cells, mistakes are made and errors start
to build up, and so as those errors start
to build up, the cells can start to grow
out of control, and that's what cancer is.
And so this is how it generally happens
in the population. In hereditary cancer,
you are born with that first insult.
So as the insults start to build up,
cancer can develop, and it
happens sooner because you were already
born with that first hit. So this is
Henry Lynch, and he's called the
Father of Hereditary Cancer, and he
started looking at these families in
Nebraska, and he luckily had these
families in these rural areas that lived
too close together, and he could gather
all of these families and gather samples
from the whole family. He started to see
a pattern of tumors that they had and
started to say, "You know, I really think
these families were born with something.
I think there's an inherited risk here,"
and really, that thought in the 60s and
70s was, "No, cancer's caused
by asbestos," and things like that. But he
said, 'No, I really think that there's
something here," and a lot of the
work that he did to create these family
trees and to collect these samples built
on the discoveries of the brca1 and 2
breast cancer genes that have also been
associated with many other types of
tumors. It built on the work that we use
for these genes today. So, when we talk
about Lynch syndrome, we are talking
about genes that are involved in DNA
mismatch repair. So when your DNA copies
itself, it has mechanisms for correcting
errors that are made, and so these
mismatch repair genes, they go in and
they correct those mistakes. So you can
imagine if one of them is not working
the way that it should, and these errors
or these mistakes start to build up,
that's when cancer can develop. This is
an example of a family that has Lynch
syndrome. So, our proband here, or our
patient that we're speaking with, with
the arrow next to him,
colorectal cancer was diagnosed at age
30, his mom had colorectal cancer at 42
and uterine cancer at 45, his maternal
aunt had uterine cancer at 35, and his
maternal grandmother had colorectal
cancer at 52. And so this is the example of a
family I would see in the clinic, and we
would run genetic testing. So, you can see
that these hereditary cancer syndromes
affect men and women, and because colon
cancer affects men and women and also a
variety of tumor types, the criteria that
we used to use before genetic testing
was as available as it is today
was the Amsterdam criteria for Lynch
syndrome. So, 3 Lynch related cancers--we
have 4 in this family--two generations
affected and one person
under the age of 50. So, these are the
cancer risks that have been associated
with Lynch syndrome. You can see
mainly the risks are for colon and for uterine
cancer, but we see that individuals can
develop bladder cancer, gastric cancer,
pancreatic, small bowel, and even breast
cancer. There's a little bit of debate on
if breast cancer is involved in the
Lynch syndrome spectrum because breast
cancer is so common in the general
population. So, these are the surveillance
guidelines, just a brief slide about
the surveillance guidelines for
individuals with Lynch syndrome.
So, the colonoscopies start at age 20 to
25, and they happen more often--every 1
or 2 years. There's also data to
suggest that aspirin may decrease the
risk of colorectal cancer in Lynch
syndrome, but the dosage has not been
determined yet. So, uterine cancer has
been associated, and also ovarian cancer,
so we educate patients about the signs
and symptoms of uterine cancer and
ovarian cancer. Ovarian cancer is quite
tricky because we do not have effective
screening for ovarian cancer. We have a
transvaginal ultrasound, but it only
detects the tumor when it is large
enough to change the shape of the ovary,
and it has progressed at that point. And
so with Lynch syndrome, we have to really
have a discussion with the family. Is
there ovarian cancer in the family? How
young is that ovarian cancer?
There have not been definitive
recommendations for removing the ovaries,
but there could be that consideration.
For uterine cancer, considering
endometrial sampling. So as far as cancer of
the stomach and small bowel, these are
also personalized recommendations, you
know, is there gastric cancer in the
family, or is that patient of Asian
descent and of a higher risk to develop
gastric cancer anyway. So that
screening can also be considered. Also,
brain tumors have been associated with
Lynch syndrome, so we suggest that
patients have a neurologic exam that is
hooked to their physical. So, why do we do
these colonoscopies so early? In the
general population, polyps transform into
cancer in about five to ten years. What
we see in Lynch syndrome is that
interval is shorter, and the
transformation happens faster, and so we
need--because Lynch syndrome happens at
a younger age, we need to start these
colonoscopies sooner and have them more
often to remove those polyps. So, another
syndrome that I mentioned earlier is
called Peutz Jegher syndrome, and it's
associated with the STK11 gene. This is
an autosomal dominant condition. It's a
pretty rare condition. Interestingly, it
has skin features associated with the
many tumor types, and so we ask some
questions about skin features. It usually
presents in childhood.
So, the tumors associated with Peutz
Jegher syndrome--we see colorectal tumors,
we see gastric tumors, small bowel, we see
some breast cancer, some benign sex cord
tumors of the ovary, pancreatic cancer--we
do see cervical cancer, but it is a very
rare type of tumor, it's not the
traditional cervical cancer that you're
going to hear about--so that's what we do
when we're investigating with a family,
you know, what type of tumor was it--
uterine cancer, and
sex cord tumors of the testes. So, also in
this syndrome we can have these
particular polyps called Peutz Jegher
polyps, so that's very helpful in making
the diagnosis. You can see the
pigmentation that I was talking about. So,
they can have black marks inside the
mouth or on the hands.
So another syndrome that has been
associated with hereditary colorectal
cancer is Cowden syndrome. The gene is
called PTEN. So, this is if you think about
lots of lumps and bumps. So we've seen
breast cancer, melanoma, uterine cancer,
thyroid cancer, colorectal cancer, and
kidney cancer. These people have these
abnormal skin growths--you know, everybody
has a few skin tags--they have many skin
tags, they have these marks called trichilemmomas,
macrocephaly--so macrocephaly
is a large head size--so we ask the
question, "Do you have a hard time finding
hats?" and we measure a head size because
that is the pathognomonic feature, or a
classic feature, for Cowden syndrome. So,
we see disorder in the thyroid, and a lot
of people say, "Well, I have thyroid
nodules"--pretty common in the general population--
this is why we take all of these things
into consideration to see how suspicious
we are for the particular syndrome. Also
with Cowden syndrome, we can see
developmental delay or autistic features.
So these are some of the skin
features with Cowden syndrome. You can
see there are lumps and bumps on the
tongue and lumps and bumps that you can
see on the hand here. So, this is a lipoma
found in Cowden syndrome, and some of the
bumps that we can see on the hand and on
the face. So, this is a syndrome--one of
those polyposis syndromes that I
referred to earlier, familial adenomatous
polyposis--so, this brings us to an
interesting inheritance pattern in
genetics. These people can have a de novo
mutation, so what that means is that they
did not inherit this mutation from their
mother or their father, it actually was a
new mutation in the sperm cell or the
egg cell that created them, and so we
won't see a family history. These people
can have tens to thousands of polyps in
their colon, and eventually if the polyp
burden becomes too high, aggressive
surgery would be indicated. You can see
that the ages of onset can be quite
young, and there is a 100%
risk for colon cancer if these people
are not treated. So with FAP, the average
age of diagnosis is 39. These people can
have duodenal cancer, they can also have
this feature of the retina--congenital
hypertrophy of retinal pigment
epithelium--so it's like a freckle on
your eye. So, we often get these referrals
from ophthalmology that this person has
a CHRPE, and maybe they have a family
history of colorectal cancer, so this is
when we all come together to work as a
team to identify hereditary colorectal
cancer, and so these patients can come in
for an evaluation. Hepatoblastoma can be
seen in FAP. 10% of children with this
tumor have FAP. So, you hear I'm starting
to talk about children, and I'll address
that soon. Thyroid cancer can also be
seen with FAP. So, when we start talking
about children, we have many things to
consider. So, if you had a family with
Lynch syndrome and, say, the age of
diagnosis for the colorectal cancer or
the uterine cancer was age 40, so what we
are seeing is that that would be what we
consider an adult onset condition, and we
would not need to test children. However,
in these syndromes, like in FAP, if a
father was positive and
had two children--say they were seven and
ten--they would be at risk for colon
polyps, and if they tested negative, they
could avoid a colonoscopy procedure, and
so that is the situation where we have
medical management that would change, and
that intervention reduces mortality. And
so we do test children in that
situation where it would change their
medical management. So, these are some
of the newer genes that have been
associated with hereditary colorectal
cancer. Polymerase proofreading
associated polyposis--so, these genes POLE and POLD1, they are very similar to
the mismatch repair genes in that they
act as a spellcheck for your DNA,
correcting those mistakes. In these
syndromes where people have mutations in
POLE and POLD1, they can have
multiple colorectal adenomas. Also, we
have seen other tumors in these families.
We've seen ovarian tumors, uterine, brain,
pancreatic, and small intestine. Another
gene that we've seen associated that is
newer is the NTHL1-associated tumor
syndrome. It's characterized by multiple
colorectal adenomas and colon cancer, and this has an autosomal recessive inheritance where you would need
to inherit a mutation from your mother and
your father to come together to cause
this syndrome. 14 different tumor types
have been reported in individuals with
two mutations in NTHL-1. So, GREM1--
GREM1-associated mixed polyposis--so,
this is a bit different. These families
not only have one type of polyp, but many
types of polyps in their family history.
So, this was originally identified in a
large Ashkenazi Jewish family that was
found--they were found to have a 40
kilobase duplication upstream of GREM1.
Since that time, more duplications have
been identified in
this mixed polyposis GREM1 syndrome. So,
there was a 14 kilobase duplication.
There was a duplication of the whole
gene in one circumstance. So, the 40
kilobase duplication has been detected
in one of 184 Ashkenazi Jewish
individuals with a personal or family
history of polyposis or colorectal
cancer. So, these families had these
different types of polyps, they had
adenomas, they had hyperplastic polyps,
they had juvenile polyps, and it's
important to keep in mind that when we
talk about a juvenile polyp--a juvenile
polyp does not refer to the age of onset,
but rather the histology of the polyp, so
with GREM1-associated mixed polyposis,
the data has shown us that the typical
age of onset of polyps is in the late
20s or older. However, there have been
polyps in individuals at ages 10, 16, and
18, so this is one of those situations
where we have to take a thorough family
history because we're really adding to
the data at this point about what these
genes look like and how they are
behaving in families. The NCCN guidelines
recommends starting colonoscopies in the
20s, but if you have a family history
where there have been childhood polyps,
we need to ask about when these
colonoscopies started and when these
polyps started. So, another gene, RNF43--it has been associated with a
serrated polyposis syndrome, so this--due
to the scarce data that we have on this
gene--and it is an extremely rare
syndrome associated with a high risk for
these serrated polyps, and we haven't
seen other tumors associated with
mutations in these genes--up to date, we
have identified a total of 13 carriers
in seven families.
The mean age of diagnosis is 44 for
colorectal cancer. So, when we talk about
genetic testing, I've talked a lot about
positive results, so this is when we can
start characterizing these genes. In
reality, when we do genetic testing, most
of the time we get a negative test
results, so let me go over with you the
types of test results that we get. So, the
positive test result is when we identify
this hereditary syndrome, we can warn
other family members that this syndrome
has been identified, and they can pursue
testing if they want to, so a positive
often is pretty helpful in why did this
cancer happen, and now what are we going
to do for you to tailor your screening
and to help your family members. A
negative test result is when we look at
this whole list of genes associated with
hereditary cancer, and we do not find any
mutations associated with hereditary
cancer. In that scenario, I need patients
to keep in mind that we are just testing
the genes that we know about today. We
know that there are other genes down the
road that we are going to discover
associated with hereditary cancer, and so
if a patient tests negative, we say, you
know, check back with us in a few years,
I'm sure we will have updated testing
with new genes to test for. Additionally,
our testing technology is only as good
as it is today, and so we know that our
testing technology is going to improve,
we know that families have mutations
that we are not picking up today, that
improved technology might pick up down
the road, so I say all that to tell you
that a negative test result does not
rule out hereditary cancer. It tells us
we have no evidence of hereditary cancer
at this time. So then the last possible
test result, which is a difficult one to
deal with, is a variant of uncertain
significance. Sometimes when we run
testing, the laboratory can find a
genetic change that they do not have
enough data to tell us what it does in
the body, they cannot tell us if it is
normal human variation
or if it is a cancer-causing change, and
patients will often say to me, "Well, I
have colon cancer and I have this
genetic change, so it must be associated
with the cancer-causing change," and I
tell them that we are sampling a biased
data set because we are testing
individuals that have cancer, we are
testing families with a large family
history of cancer, and so we cannot say
definitively that it is a cancer-causing
change because we do not have the data
we have to compare it to populations
without cancer. We have to make mouse
models and yeast models to determine
what that change is actually doing, and
so when we find these variants of
uncertain significance, we have to treat
them like a negative test result because
we just don't know what it's doing in
the body, and we can't make
recommendations based on information on
data that is incomplete. When this
happens, the laboratory does keep the
data, and if they ever reclassified the
change as positive or negative, they make
us aware, and then we recontact patients.
Most of the time, these genetic changes
turn out to be absolutely nothing, about
90% of the time. So, in summary, the most
common cause of hereditary colorectal
cancer is Lynch syndrome. Here's a list
of just some of the genes that have been
associated with hereditary colorectal
cancer. The reason that we do testing,
that we walk patients and families
through this process, is really to take
care of the whole family, because genetic
testing can help direct care and provide
guidance for family members on when
screening should start and how often
screening should happen, and I should say
that a genetic counseling visit is
really about counseling, about if genetic
testing is appropriate. We don't run
testing on all patients, so it's really
looking at that family history and
making personalized recommendations, even
if it just means, well, you should do
standard screening recommendation.
Sometimes we have that too. So, I believe
we have some questions, and I'm happy to
address those. Ah, so "Is genetic testing
expensive?" I get this question a lot. So,
it's very exciting in the last few years
that the cost of genetic testing has
gone down dramatically. So, I can run a
hereditary cancer panel for $250,
even if the patient does not qualify
under their insurance. So, that does make
it affordable for more families to gain
this information. Also, many insurance
companies are expanding their testing
criteria, and testing can be covered by
insurance if you meet certain criteria.
Oh, "Is it covered by insurance?" So, yes,
each insurance company has
certain criteria, and they usually follow
national guidelines to determine if
genetic testing is necessary and if
it's likely to give us a test result.
That's why, when we take a family history,
we take all of the tumors that have been
diagnosed in men, women, children, and we
don't just look at the maternal side of
the family, we look at both sides of the
family because even these brca1 and
brca2 genes can be inherited through the
father's side of the family, and 50% of the
time, they are, and also men can get
breast cancer.
All right, so direct consumer testing. I
get this a lot. They'll say, "Oh, I did
testing where I spit in a tube and
I sent it in." I want to tell people that
there are many different testing venues
available, and some of them do not
provide the most comprehensive testing
for hereditary cancer, so sitting down
with the genetics professional is really
your best bet to tailor your testing to
your particular family history. All right,
so, thank you so much for joining us.
