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Next I'd like to talk about hereditary
cancers.
So we know that cancer is a genetic
disease.
It's always a genetic disease.
It involves mutations that occur at the
level of DNA.
But these mutations are ones that occur at
the level of an individual cell.
They're called somatic mutations, but some
cancers are, in fact, inherited.
They're caused by mutations that occur in
the germ cells, so the sperm or the egg,
and those are passed down, so a person
starts with a cell that already has a
mutation.
But additional mutations are then acquired
in
an individual cell to ultimately cause
cancer.
So while all cancer is genetic, not all
cancer is hereditary.
So what do we know about the heritability
of cancers?
Well, we know that some cancers run in
families and others not so much.
One of the ways that we measure
heritability is through a familial
recurrence risk.
What we do there is ask for a patient who
has cancer.
What is the risk that their sibling also
has cancer, and
how does that compared to the risk in that
average population.
We take a ratio of that risk to the
sibling,
and the risk in the general population,
and that's the sibling
recurrence risk in this case, but you
could use any
other family members and that would be a
Familial Recurrence Risk.
This one study by Risch in 2001 looked at
the Familial Risk of Cancer.
From two different sets of families, and I
have those plotted out here.
There were some commonalities between the
two groups
of families, but other places where they
differed.
A couple things I wanted to point out.
For example, testicular cancer shows a
very high
familial recurrence risk in both sets of
families.
But for other cancers, there's not such
great concordance.
One disease that we know has a familial
nature is breast cancer.
And the studies show a two to four-fold
increased
risk to siblings of patients who have
familial breast cancer.
So speaking of familial disease, I want to
next talk about family history
and how and when we consider taking a
family history of patients and
how that relates to breast and colon
cancer in particular.
So when we talk about family history
of cancer, we usually take those at
diagnosis.
So here's a family and here's our patient
if they were diagnosed with cancer, we
would
want to get a complete family history at
that point, and then update it regularly
over time.
We would like to ask about first and
second-degree relatives.
First-degree relatives being siblings
parents and
any offspring that they might have.
But, history in extended relatives, as
well, such as grandparents, aunts
and uncles and cousins, is also going to
be important, so.
Asking about cancer in both first degree
and second degree relatives is key.
And then for each of those family members
who have cancer, such as shown here, we
would
want to determine what was the primary
type of
cancer, what was their age at diagnosis,
the lineage.
So you want to know if it came from the
maternal side or the paternal side.
The ethnicity, because some cancers are
more common in different ethnic groups
such
as Ashkenazi Jewish population has an
increased
risk of breast cancer from BRCA1
mutations.
And finally, the results of any genetic
testing that was done in that family.
So how will we recognize a hereditary
cancer?
Well, if you think about an individual
patient, some of the characteristics that
might
lead you to think that there is a familiar
or hereditary basis for the cancer.
Is if they have multiple primary tumors in
the same organ, or different organs.
So different cells have become mutated at
different times,
and generated the two distinct, two or
more distinct cancers.
Another clue might be bilateral primary
tumors,
such as in the case with breast cancer.
If you have a tumor that originates in
both breasts
independently, that's an indication that
this might be an inherited cancer.
A younger than usual age of onset for a
tumor diagnosis
is also one of the keys that a cancer
might be genetic.
If you have a tumor that has a rare
histology that's not very, very commonly
noticed that might also
be some indication that there's a genetic
component, as well
as tumors that occurs in the sex not
usually affected.
Think about breast cancer that occurs in
males, which is possible,
that's some indication that that may be a
genetic or inherited cancer.
And then when you look at the patient's
family, you
want to look for first degree relatives
with the same tumor history.
So all of these are clues, they're red
flags,
that you may be looking at an inherited
cancer.
So I'm going to talk briefly about the
hereditary basis of two cancers, breast
cancer
and colon cancer, since those are the ones
that we've made the most progress on.
If you think about breast cancer the risk
is about 1 in, 1 in 10 so about a 12, 1
in 9 or 10, about a 10 or 12% chance of
developing breast cancer in your life.
And first degree family history of breast
cancer actually increases your risk about
two fold.
Now, only about 5 to 10% of breast cancer
is hereditary.
So in other words, most breast cancer, 90%
of breast cancer is sporadic.
Having a family history will not tell you
anything.
What do we know about the inheritance?
Well, we know a lot more than we know
about other cancers.
We know that the inheritance of breast
cancer, it acts as a complex disease.
We've talked a lot about complex diseases
and how there are genes
and there are environmental factors that
cause the cancer, and cause the disease.
And that's true for breast cancer, as
well.
But there are forms of breast cancer that
appear to act in
a Mendelian fashion, such as those due to
mutations in BRCA1 and BRCA2.
These are genes that are indicative of
hereditary breast and ovarian
cancer, but those aren't the only genes
involved in breast cancer.
If you look at what we know about the
genetics of breast cancer, we still
are unable to explain about half of the
hereditary basis of breast cancer.
The BRCA1 and 2 genes account for only
about 15% of inherited breast cancer.
Then we have mutations in other genes that
behave in a Mendelian fashion.
Parts of cancer syndromes were breast
cancers manifestation.
And then we have other polymorphisms that
have come out of genome
mod asssociation studies where they confer
a slightly increased risk of breast
cancer.
So, all of this together gives you a good
picture
of what we know about the genetics of
hereditary breast cancer.
What about hereditary colon cancer?
Well, we know that a family history of
colon
cancer increases a patient's risk about
two- to fourfold.
There are a couple of different types
of hereditary colon cancer that have been
described.
One of them is familial adenomatous
polyposis or FAP for short.
You can see the histology of the cancer
here or what, what the colon actually
looks like.
These people have hundreds and hundreds of
polyps that occur along their colon.
And the chance is high that at least one
of these will turn cancerous.
This disease is due to mutations in a gene
called APC.
There is another type of hereditary colon
cancer called HNPCC, which
is also called Lynch Syndrome, and this is
due to mutations in DNA repair
enzymes specifically these DNA repair
enzymes MLH1 and MSH2 and others.
And when these are mutated, they cause
non-polyposis type of cancer.
This accounts for about 2 to 5% of the
total burden of colorectal cancer.
So these are two types of inherited colon
cancer.
And we're able to offer testing for these
in the clinic as well.
What do we know about the genes involved
in inherited cancers?
We know that some of these are
tumor suppressor genes, and tumor
suppressor genes
act at the recessive level in a recessive
fashion at the level of the cell.
In other words, both copies of the gene
need to
be mutated in order for them to have an
effect.
But at the pedigree level or at the
individual level, they act as a dominant
trait.
What do I mean by that?
Well to explain this we have to look at
this Knudson's two hit hypothesis for
tumor suppressor genes.
This hypothesis states that a cancer, a
tumor suppressor
gene requires two mutations and, and in a
cancer, in
a sporadic cancer as opposed to a familial
one, these
two mutations are acquired over the course
of a lifetime.
So you have your normal pair of
chromosomes or
normal set of, of the tumor suppressor
gene, normal pair.
And one copy of that gene becomes mutated
and then at some later time the other
gene becomes mutated so now both copies
are
mutated, and that allows the cancer to
develop.
What happens in an inherited cancer is
you're born with one mutated copy already.
So you go through your life only needing
to acquire one
additional mutation in that gene, and when
that happens you develop cancer.
And you can see how this explains why
these
cancers have an earlier age of onset as
well.
Okay.
Besides inherited breast and colorectal
cancer, there are also inherited
familial cancer syndromes, and I have
several of them listed here.
These are syndromes where, you have one
gene that's mutated.
For example TP53, which leads to what's
called Li-Fraumeni disease, which is an
inherited
cancer syndrome where family members can
have
any one of a number of different cancers.
Leukemia, breast, brain, soft tissue
cancers.
So, in the pedigree, it's not a homogenous
cancer.
Here's an example of what a Li-Fraumeni
pedigree looks like.
And you can see the diversity of different
cancers in that pedigree.
Now you see a lot of cancer, which is your
clue
that this is an inherited cancer, but it
is again diverse.
The next few slides I'm going to provide
you
with some information, and it's quite
detailed so I
just wanted to mention a couple of things
and
you can look, look them over in your
leisure.
But, one of the things is when to seek
genetic counselling even in the absence of
a family history.
There might be certain clinical situations
where, for example, you have somebody
who has a triple negative breast cancer,
which I'll explain in subsequent slides.
Or other characteristics of their cancer,
which may lead you to suspect that this is
indeed an inherited form of disease, even
in the absence of family history.
Similarly having rare tumors and pediatric
cancers are all indications when
you may want to seek the counsel of a
genetics professional.
There are also various risk assessment
models that could be
used to determine whether your patient
should undergo genetic testing.
And I have those listed here.
Genetic tests are currently available for
Lynch syndrome,
the inherited colorectal cancer, inherited
breast and ovarian cancer.
Melanoma Li-Fraumeni, and Cowden, both
cancer
syndromes as well as some other tests.
But there are, like I said, some risk
assessment models that can be used ahead
of time in order to determine whether
your, your patient is a candidate for
testing.
And finally, I've provided you with
some resources for locating cancer genetic
specialists,
a number of different websites that can be
used to identify these people.
And one last thing that I wanted to
mention, if you decide to undergo
genetic testing, for known cancer
susceptibility genes,
a couple things to keep in mind.
First of all, a negative test result is
no guarantee that the cancer will not
develop.
We already know that inherited cancers
account for
a very small portion portion of cancer
burden.
So the chances of a person developing
cancer are still pretty much
it, it as high as they were before you got
the genetic testing.
So, keep that in mind, it does not
guarantee that you will not develop the
cancer.
Similarly, a positive test result is no
guarantee that the cancer will develop.
Early on when we discovered the breast
cancer genes
BRCA1 and BRCA2, they were discovered
using high risk families.
People who had pedigrees where there were
multiple effected individuals and so the
penetrance the
probability of getting disease if you had
a
mutation, was actually estimated to be
quite high.
As high as 80% in your lifetime.
But now, those estimates have come down,
because we've been able to evaluate more
people.
We've taken different ascertainment
strategies, and this has actually helped
us to come up with more accurate estimates
of risk.
So, having a cancer predisposing mutation
is
no guarantee that you will develop cancer.
Finally, what can you do if you have a
mutation?
Well, there's several risk management
strategies that
can be undertaken for a positive test.
And again, using the breast cancer
example.
If you are positive for BRCA1, you can
increase surveillance.
In other words, do more mammograms and
screening.
There's also the possibility of initiating
prophylactic hormone therapy, lifestyle
changes, and
we know diet and exercise can increase, or
influence your risk of cancer.
And finally, prophylactic surgeries.
Prophylactic imogr,
mastectomies, and a nephrectomies can help
reduce your risk, of breast
and ovarian cancer if you carry a
mutation, in this gene.
Now I have a question for you.
Cancer is primarily due to which type of
mutations, somatic or germline?
The answer is the cancer is always a
somatic disease, and only 5
to 10% of cancers are inherited or due to
mutations in the germline.
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