Hereditary Colorectal Cancer

Hereditary Colorectal Cancer

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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.

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