Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.
A Family Member With Colon Cancer
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来自 Vanderbilt University 的课程
Case Studies in Personalized Medicine
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从本节课中
UNIT 4: CASE STUDIES IN PERSONALIZED MEDICINE, PART 2
Module 7 continues our focus on case studies with a look at some cases that illustrate how personalized medicine informs treatment decisions related to specific diseases/conditions. These include cystic fibrosis, Marfan syndrome, heart failure, neuropsychiatric diseases, and diabetes. Three cases/lessons focus specifically on how genomic medicine informs testing for and treatment of cancer.
与讲师见面
Dan Roden, M.D.Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine
[MUSIC]
Today I'm going to continue the theme of family cancer susceptibility and
we're going to start with a case of a woman who comes to you,
she's 25 years old and she says, my father died of colon cancer when he was 47.
Do I need to be worried?
So the first thing that we do in a situation like this is we
ask the details of the father's history, the mother's history, and go back through
the rest of the family and ask if there's any other cancer or any other diseases.
And when we do that in this particular In case we find that an aunt has uterine
cancer and then the father's father also had colon cancer.
So this is a family that you'd have to worry that there's something going on
here that would make them susceptible to colon cancer.
Colon cancer, just to review,
is the second leading cause of cancer death in the United States.
These are separated on this particular slide by mortality in men and women.
Lung cancer, unfortunately, is by far, the leader.
And then in men, prostate and in women, breast cancer comes in second, but
colorectal comes in third for both and so across the United States, colorectal
cancer is the second leading cause of cancer deaths in men and in women.
Colon cancer, like breast cancer often has a family history component and
you can separate that into people who have real genetic syndromes five to 10%
of patients who will have a history like the one I just showed you.
And then another group of patients who have a very strong family history,
a suggestive family history, in whom we don't find a gene.
And then the sporadic cases in green where
we wonder if there could be a genetic risk factor.
But there's not anything in the family that suggests that there is.
The major syndromes that predispose to colon cancer, Lynch syndrome,
which I'm going to talk a little bit about,
the Familial adenomatuous polyposis syndrome, FAP, is also mentioned and
then there's something called Gardner syndrome is a variant of FAP.
Lynch syndrome, describe in 1966 by Lynch Two to 3% of all colorectal cancers.
Typically in the right colon,
the ascending colon, sometimes with multiple primaries, polyps can be present.
It's an autosomal dominant disease.
The lifetime risk of cancer is 80% so this is highly penetrate.
It doesn't mean that you going to get colon cancer when you're 25, but
if you live to be 90 you will have a high, high likelihood of getting colon cancer.
There is an association with many other forms of cancer,
including endometrial cancer As in this particular patient, gastric cancer or
ovarian cancer and other GI tract cancers, and a smattering of other cancers as well.
Lynch syndrome is now understood to be a disease of defective DNA mismatch repair,
so there's this idea that cells, when they replicate, sometimes don't get the DNA
exactly replicated right but they have mechanisms to fix that.
In the case, in this case here, for example, the replication
of the T Strand should result in an A but occasionally results in a G.
So the body has mechanisms to correct that G back to an A and
not let that mutation accumulate over time.
And one of the genes that's involved in that is shown
here on the bottom in a crystal structure and it's MSH6,
which is the most commonly mutated gene in Lynch syndrome.
So, the problem in Lynch syndrome is a problem of defective DNA mismatch repair.
There are many other genes involved, but 90% of the mutations are caused by,
90% of the cases are caused by mutations in MSH6 or M MLH1.
The pathological characteristic is microsatellite instability which is
something that can be detected by the pathologist using DNA sequence analysis.
And the diagnosis is either by germline genetic testing to find a mutation in
MSH6, MLH1, or other Lynch syndrome associated genes, or
by analysis of the tumor itself, to detect these mutations and
the microsatellite instability.
So faced with a patient like the one that I presented to you, the question is,
should they have genetic testing for Lynch syndrome or not?
And there are criteria that have been set out to
identify patients who have a high likelihood of having a positive test.
And those criteria are the so called Amsterdam II criteria.
There are other criteria that have been described and there are so
called the 321 criteria.
So at least three relatives with colorectal or
other Lynch syndrome associated cancers, this patient has that.
At least two successive generations, this patient has that.
And at least one relative diagnosed before age 50, this patient has that as well.
You need to eliminate the diagnosis of Familial adenomatous polyposis, and
it would be desirable to have the tumors verified by pathology.
So faced with a patient like this, it's no different from a patient with
a cardiomyopathy risk or an arrhythmia risk or breast cancer risk.
The best person in whom to do the genetic testing is the person who has the cancer
and in whom we can make or not make the diagnosis of Lynch Syndrome.
And then we can ask the question is the relative at risk or not because we could
say does the relative have the mutation that the patient who has the disease has.
In this particular case, we don't have that luxury
because the patient the closest relative has died of colon cancer.
And that is often the case.
We're faced with testing people in whom there's no cancer yet
and in whom if we find a mutation we're never sure whether that mutation
might be a benign fellow traveler or might be a causative mutation.
So again, this is the problem that we face in a family like this.
So the management in this particular case is genetic testing
in the affected individual, if possible.
If not, then this particular young
woman should get genetic testing based on the Amsterdam II criteria.
And if they have a mutation that is known to be pathogenic
in one of those two Lynch syndrome genes or others.
Then you can diagnose them as having increased cancer susceptibility.
So if the genetic testing is positive, then colonoscopy every year or
two starting at a very young age.
The age is either 20 to 25 something like that or
ten years earlier than the earliest case of colon cancer in the family.
So the earliest case of colon cancer in this family was 47 so this person would
start colonoscopies at age 37 or 25 whichever is younger, so age 20 or 25.
And because this person is a woman and there's a risk of uterine cancer as well,
gynecological exams, including the potential for trans-vaginal ultrasounds or
testing of cancer markers that are circulating in the blood stream, Ca125,
starting again at a relatively young age to detect early, and to treat early.
The other disease that is much rarer but
has an exuberant clinical phenotype is familial adenomatous polyposis.
Very rare.
Autosomal dominant, so a single gene mutation will cause this.
And the mutation is in a gene called APC, which is a tumor suppressor gene.
So again, you have a mutation in a tumor suppressor gene that
wipes out its function.
And all you need is a mutation in the other form of the tumor suppressor gene
and suddenly you have no tumor suppression capability.
The pathological or the clinical hallmark of this disease is carpeting,
literally carpeting of the colonic mucosa by polyps.
Very, very high likelihood of colon cancer by age 50 with
other cancers that are listed here, stomach cancer, small bowel cancer,
pancreas, thyroid, and hepatoblastoma in children.
So that has implications for screening for cancers along the way.
So the management of a person who's an FAP mutation carrier is sigmoidoscopy
starting off at a very young age and
once polyp polyps are detected, probably a prophylactic colectomy and
you still have to pay attention to the ileal pouch and to the rectal remnant.
To make sure that
they're not developing polyps in those areas and have a cancer risk as well.
Because of the risk of stomach and small bowel malignancies, upper GI endoscopy
starting at age 25 and then every so often after that and in infants and
in children screening for hepatoblastoma up until age five with ultrasound.
On an alpha-fetoprotein measurements in the endoplasma.
So I've gone over now two cases of breast cancer
susceptibility in the previous module and colon cancer susceptibility here.
And the problem is one, identifying
patients who need to have referrals to specialized cancer genetic clinics.
So that's the small five to10% slice.
Perhaps the pink slice as well, the strong family history slice,
although there's a chunk of those in whom we don't find mutations at this point.
The big public health problem, of course, is the green part.
And again colon cancer is one of the leading causes mortality so
we've been focused on personalizing medicine but
there's also an aspect to this that is preventive medicine and
what do you do about preventing colon cancer a leading cause of death leading
preventable cause of death In the United States.
So there are guidelines from the Canadian Cancer Society
that are difficult to read on this slide, but lay out for
you what you should do in terms of screening people for
genetic risk, high risk, medium risk, and low risk.
But the most interesting category of all are the people who are at population risk.
Because its the people who are at population risk who make up the vast
majority of death from colon cancer.
It it says meets know the criteria for genetic testing but
still have Has a one in 16 lifetime chance of developing colorectal cancer.
So the recommendations for genetic screening are interesting and
part of personalizing medicine, but we shouldn't loose sight of the fact that
this is a really highly prevalent disease and if managed correctly entirely or
largely preventable at least in terms of deaths.
And the way it's prevented is by annual stool fecal occult blood and
regular examinations of the colon by x-rays or
by colonoscopies starting at age 50,
and that's the recommendation in the bottom green set of panels.
So personalizing medicine is important.
It's important to pick out people in whom special different kinds of approaches need
to be used.
But we shouldn't lose sight of that fact that this is
a largely preventable disease if appropriate prophylaxis is put in place.
So I think there are two bottom line messages here.
[APPLAUSE]
