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So we're going to start by

talking about genetics,


where it shows up in medicine and
public health.
But let me first pause and
talk about this term precision medicine.
What do we mean by it?
In fact it's a term that's
just recently come into use.
Like many new terms, it has different
meanings to different people.
and, I'm giving you
a couple of definitions.
One of them is from the UCSF website.
Talking about precision medicine
as the use of molecular tools.
To make medicine more predictive,
preventive and
precise, those are important
words to have in mind as we
think about what precision medicine can
do, and what challenges it might bring.
Another definition on the web.
Emphasizes that the patient is at
the center of precision medicine, and
also notes that precision medicine
is not just genomic information or
molecular information.
But also other information
including environmental data,
that might be relevant to
a patient's health care.
and, and, this definition of
precision medicine, I think,
starts from, an important base.
Which is that information is really
at the center of healthcare.
we, as we deliver healthcare,
as we take care of patients.
As we deliver public health interventions.
We start by gathering information
to help figure out what to do.
We base interventions on the information
that we gather and then when
we implement an intervention, we gather
information to figure out how it worked.
So the premise of precision
medicine is really a premise about
more precise information.
In order to enable us to do more and
do better.
And at the heart of it is a,
an amazing technologic development, which
is the ability to gather information about
people's whole genomes and whole exomes.
So whole genome is the full
DNA sequence of an individual.
We now have relatively efficient and
cost effective methods to
gather that information.

A whole exome simply refers to


the subset within the genome which is
the protein coding genes.
So, the technical ability to gather
this information delivers to clinicians
a huge additional amount of information
that was previously not available.
And drives a lot of the thinking
about this new opportunity.
And there are related
molecular opportunities.
We now can measure gene
expression profiles and
increasingly, we have the ability to do
proteomic measurements, that is measuring
proteins in the body and, and
also a wide range of other metabolites.
So we're on the cusp of technical opp,
opportunities to gather
huge amounts of information and
to use them in clinical care.
And the question is, how do we use that
information in ways that enhance our
ability, and what kinds of challenges,
might this information pose?
So, we're going to start by thinking
about how we use genetics now.
And I'm going to start with a story,
and this is a story of a young boy.
Who has vision bli, vision loss.
He started with night blindness.
Great inability to see, at nighttime.
And his vision loss has
steadily progressed.
He's still a young boy.
He's gone to the ophthalmologist.
And the ophthalmologist has
done a very careful eye exam.
And has found out that he has a retinal
degenerative condition called
retinitis pigmentosa.
This is an interesting condition,
determined by genes.
People who have variations in
multiple different genes can
develop this retinal
degenerative condition.
And in terms of the genetics of retina,
retinitis pigmentosa more
than 40 genes are involved.
And one of the really interesting things
about that, those many genes are, that
are involved, is that they present in a
variety of different inheritance patterns.
So we have retinitis pigmentosa
inherited as an X-linked recessive,
in which moms are carriers and
can pass on to affected sons.
We have autosomal dominant forms, in which
the inheritance goes from parent to child.

And we have autosomal recessive forms,


in which two parents are carriers, but
can pass on this state to their children.
And genetic testing now can
help us to sort out for
any given person whose exam tells us that
ret, retinitis pigmentosa is present.
What kind of inheritance pre,
pattern is present in that family.
And we'll talk why that matters, in fact,
for the boy we're concerned about who
has vision loss, genetic testing reveals
he has a mutation in the RPGR gene.
And that tells us he has
X-linked retinitis pigmentosa.
And in fact his family
history confirms that.
We see from his family history that there
was an uncle who had the same condition,
his mother is a carrier, and
has passed this condition on to him.
Why does it matter that he has
X-linked retinitis pigmentosa?
Well, it turns out this, this information
is very useful prognostically.
People with, retinitis pigmentosa
can have a wide range of severity.
And a wide range of time course for
their loss of vision.
Some people, only notice bothersome
vision loss in their 30's and 40's.
But other people can have
very severe vision loss.
And in fact, X-linked retinitis pigmentosa
is on the severe end of the spectrum.
Knowing that he has this form
of retinitis pigmentosa,
based on the genetic test result,
we're able to predict that he is going
to be legally blind by the time he's 20.
We don't, unfortunately,
have any treatment that will change
the course of his vision loss.
But the information can be
useful in a variety of ways.
First of all, it helps to know this
in terms of his education plan,
in terms of his career planning.
This is someone who wants to plan for
a career that will not be
dependent upon vision.
He may want to be sure that he lives in
an urban environment where services will
the there, available to him as a,
a vision impaired individual.
So the information has a lot of value
to him socially and to his family.
And also because he knows what he has,
he can use that knowledge to find
others with similar problems perhaps.

Have opportunities for support and for


sharing experience, so this is
where a lot of medical genetics is.
We can identify what the genetic problem
is, we can help people to plan for
the future.
We have only limited abilities to
change the course of the disease,
never the less the genetic
information can be helpful.
And sometimes it can be a little more
than information so a very common use
of genetic testing nowadays is
to assess inherited cancer risk.
And I'm showing you here a family that
represents what we call hereditary breast,
ovarian cancer, a particular condition
associated with mutations in the BRCA1,
and BRCA2 genes.
Here we have a family where
the grandmother died of ovarian cancer
the mother has breast cancer and,
and developed it in her 40's and
she now has a daughter who's
had breast cancer in her 30's.
This is a situation in which
genetic testing is reasonable.
To see whether a BRCA1, or
BRCA2 mutation is present.
And then to council
the family accordingly.
There are a lot of reasons why it might be
useful to know if a BRCA1 mutation is, or
BRCA2 mutation is, is present.
First of all for the young woman who's
just been diagnosed with breast cancer in
her 30s,
her treatment options might change, and
she might make different choices about her
treatment options, knowing about her risk.
If she has a BRCA1 mutation, she's got
a lifetime risk of breast cancer, of,
of a second breast cancer,
that's somewhere in the 40
to 50% range after having had her
first breast cancer diagnosis.
And that may be a reason to
choose bilateral mastectomy,
in the course of her
breast cancer treatment,
rather than lumpectomy or,
mastectomy of just the affected breast.
She may also want to
consider oophorectomy.
She has a 40% to 60% lifetime
risk of ovarian cancer.
And then there are some very exciting,
data suggesting that
there may be a particular set of
medications called, PARP inhibitors.

That may have particular value,


in women, with these kinds of cancers.
That's still under study, but
there are very promising results.
The information is equally, if not
more significant, for her two sisters.
Who are not affected
with cancer at this time.
If their sister has a BRCA1 mutation,
they've got a 50/50 chance
of having one themselves.
And if they have inherited the breast
cancer gene in the family.
They have a variety of preventive
options that they may want to consider.
Again, prophylactic surgery,
early breast screening with MRI and
possibly chemoprevention with tamoxifen.
All of these may help to
reduce their cancer risks.
So here we begin to see genetic testing.
Enabling us to not just give people
information that may be useful in
planning, but actually to help guide
treatment for the problems that they face.
When we think about that family,
with a very high
rate of cancer and likelihood of inherited
risk of breast cancer, we of course,
also have to think about other genetic
causes, not just BRCA1, and BRCA2.
Part of the task of medical
genetics in fact, is recognizing
the range of genetic causes that might
contribute to a particular health problem.
In the case of breast cancer, we have
at least three other inherited forms of
cancer, where breast cancer's
part of the picture.
There's a syndrome called Li-Fraumeni
Syndrome, in which people have,
tend to have multiple cancers,
breast cancer being one of them.
There's a condition
called Cowden Syndrome,
that can cause early breast cancer.
There's a condition called Lynch Syndrome,
inherited colorectal cancer, but
sometimes family members
get breast cancer as well.
And so part of the opportunity that
new genomic technology gives us,
is the possibility to look not
just at the BRCA1 or BRCA2 gene.
But in a single test to look at
many genes to find and test for
multiple different contributors to
cancer risk, all with the same test.
That's a, just a beginning of
the opportunities that whole genome and

whole exome testing gives us.


But as the research has gone
forward in breast cancer genetics,
what we know is that in addition to the,
the conditions I'm mentioning to
you were high risks of cancer,
are part of the picture.
We are now finding many genes,
many variations in those genes,
that seem to be associated with small
increase risk of breast cancer, or
decrease risk of breast cancer.
It looks like 40, 50, or
more genes may contribute in
some way to breast cancer risk.
Most of them with a very
small additive contribution.
And one of the questions that we
face as we increasingly gather this
information is, what's the level
of risk information that's useful?
In general, in genetics,
we want to pick all of the risk factors
that are at the top of the triangle.
Those risk factors that are what
we call highly penetrant.
There's a high likelihood that if
you have a gene variant you're
going to have a problem.
Perhaps we want those moderately pren,
penetrant genes where
there's a significant risk, but do we
want to go all the way down to the base?
Do we want to find out if we're
a little bit above average or
a little bit below average for
breast cancer risk or for any other risk?
The new technologies pose this question,
we're going to have to answer it.
We're going to have to figure out
what level of risk is useful.