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Female Speaker: Kathy, would you like to introduce our speakers?
Kathleen Calzone: Yes. So we're really delighted to begin with
the Integration of Genomics in Cancer paper, and the two authors who were predominately
responsible for that paper are joining us today. And the first is Dr. Erika Santos,
and she's actually joining us from São Paulo, Brazil, and is currently working at the hospital
A.C. Camargo in their Oncology and Hereditary Colorectal Cancer program there. And in addition
to that facility, she is also the supervisor for their graduate program, and she teaches
oncology nursing. Erika is very active in the International Society of Nurses in Genetics
and is the editor of the newsletter, and she's been the editor for several years now.
And then Dr. Deborah MacDonald is also joining us, she'll speak second in this particular
presentation. And since January, Deborah's been working with me here at the National
Cancer Institute and the Center for Cancer Research in the Genetics branch. Prior to
that, she's had an illustrious career in cancer genetics, first at Massachusetts General Hospital,
and then for many years now at the City of Hope Comprehensive Cancer Center in their
Clinical Cancer Genetics program that she helped develop there with the team. She's
been a longstanding member of ISONG and was a former president of the International Society
of Nurses in Genetics. So I'm going to turn it over to the both of them.
Erika Santos: Hello to all. My name is Erika Santos. Deborah
MacDonald and I, we will talk the next 20 minutes about integration of genomics in cancer
care. On behalf of all the authors in this paper, we would like to thank NIH for this
opportunity to talk about -- with you about this issue. Next, please. Next slide.
So the aim is to introduce how genetics and genomics are integrated into cancer care from
prevention to treatment. Next.
So the presentation will cover five topics: etiology of cancer, cancer risk assessment,
tumor profiling, pharmacogenomics, and targeted cancer therapy. Next.
So we decided to use a case study approach. So Mr. J is 41 years old, European ancestry.
His biopsy showed right-side colon cancer and two polyps. He had no prior cancer history,
and his medical history was unremarkable. Next. This is Mr. J pedigree so we can see
here that he had colon cancer at the age of 41 and two polyps. His father had colon cancer
at the age of 41 -- 50. His father had -- his aunt had uterine cancer at the age of 43,
and his grandmother had colon cancer at the age of 52. So we will discuss this -- the
implication of his personal cancer history and his familial cancer history later on.
But first of all, I would like to talk with you about the etiology of cancer, and cancer
as a genetic disease. Next. So cancer is a genetic disease, is multifactorial, and infection
and chemical products and radiation alters DNA structure. So genetic and genomic factors
underlie the etiology of all cancers. Next. So it's important that we know the etiology
of cancer, you know, all risk factors that are related to the cancer development because
this is important for cancer risk assessment.
So there are different risk factors that are related to the cancer development, and nurses
must recognize those risk factors. And the radiation, chemical, and biological, and one
of the important risk factors are genetic susceptibility. Next.
So if we -- according to cancer history, family history, tumors can be classified as sporadic,
familial, and hereditary. This has very important implications for the development or the strategies
for monitoring individuals and also at-risk family members. Next. Sporadic tumors account
for 75 percent of all cancers, and usually occurs at an age of onset that is expected
for this -- the kind of cancer that we are talking about. For example, colon cancer at
age of 65. They are related to somatic mutations in a specific tissue, for example, breast
or colon cancer [unintelligible]. Next.
On the other hand, if -- sometimes we can see the same type of cancer occurring at the
expect age but in more than one close relative on the same side of the family; for example,
two siblings with colon cancer after the age of 60, or two sisters with breast cancer with
age of 65, and sometimes this is referred as familial cancer. These account for 10 to
15 percent of all cancers. And this is likely the combination of environmental and genomic
influences that are shared by close relatives, and -- or low-penetrance genes or SNPs. Next.
And 5 to 10 percent of all cancers are hereditary, and they are due to single gene mutation in
the germline that exposed an individual to developing certain cancers. The hallmark is
an early age at onset that normally would not [spelled phonetically] be expected for
a particular cancer, for example, colon cancer at age of 30, or breast cancer age of 30.
And this is, as I said, a germline mutation that is usually related to this kind of cancer.
Next.
So most germline mutation are transmitted to the offspring by the mother or the father
during conception, and somatic mutations, on the other hand, are not transmittable,
and they occur in somatic tissues. Next.
So how important is to recognize difference among acquired, inheritable genetic mutation?
This is very important because it is a key to appropriate referral and further evaluation.
And how can we achieve that? Next.
One of the tools is cancer risk assessment. Cancer risk assessment is used to define cancer
risk for clients and family members, and this is used to -- through the collection for personal
-- with personal health and family history. Through cancer risk assessment, we can identify
individuals who might benefit from genetic and genomic testing, and also we can provide
cancer screening strategies for those individuals. In cancer risk assessment is very important
tool to access psychosocial and cultural implications for cancer risk assessment. And the -- one
of the most important thing is, is to provide education, counseling, and to facilitate informed
decision making. Next.
But when we consider the cancer risk assessment, of course, it's not possible to refer all
patients to cancer risk assessment. So we need to identify those individuals who should
benefit with this strategy. So we have the red flags; so red flags are features on personal
or family history of cancer that draw attention to suspect familial or hereditary cancer.
So these are the red flags; they're only an indication for investigation. So we have here
earlier age of cancer onset than expected; same type of cancer in two or more close relatives;
two or more primary cancers in same person; and a constellation of cancers characteristic
of hereditary syndrome, for example, breast and ovarian cancer, or colon and uterine cancer;
and some male breast cancer, ovarian cancer, thyroid cancer, at any age; particular -- actually,
medullary thyroid cancer at any age, any mutation in the family.
So, if we -- next. Now we connect to our case, our pedigree. Next. We can see now the actual
case study of the pedigree of Mr. J. We can check some red flags here. So we have age
at diagnosis, earlier than expected. More than colon cancer -- three cases of colon
cancer, which is not expected here, so, we have three cases of colon cancer. And we have
also a constellation syndrome, which is uterine cancer and colon cancer, which is characteristic
of the syndrome. So based on these characteristics, Mr. J was referred for evaluation and molecular
investigation, and discuss it with the patient. So now Deborah will continue with the presentation.
Deborah MacDonald: Okay, so thank you, Erika. I'm turning to
tumor profiling. This is the evaluation of genomic factors, and not just individual genes,
but the study of one's entire genetic makeup; proteomics, the study of the structure and
function of proteins; and epigenetics are factors that can change the expression of
the gene or the physical, physiologic, or biochemical characteristics of an individual
that are not due to a change in the DNA.
So here we take our example of tumor profiling by a process known as immunohistochemistry,
or IHC. In Mr. J's case, this test is performed in the pathology lab on tumor tissue to screen
for Lynch syndrome by examining the protein expression of the four primary mismatch repair
genes that are associated with the syndrome. And as you can see, there is very little expression
of MLH1 here, protein product, as compared to the expression of the other three genes,
suggesting that the MLH1 gene could be mutated. This helps to guide genetic testing by targeting
testing to this specific gene rather than testing for all four genes, and thus it's
a more effective and a less costly strategy.
So microsatellite instability testing, or MSI, is another laboratory test that when
microsatellite instability is found, it suggests that the individual has Lynch syndrome. However,
about 10 to 15 percent of microsatellite instability is present in various sporadic cancers, so
this is a clue, as is IHC, that there could be an underlying genetic susceptibility to
colon cancer, specifically here, Lynch syndrome. MSI testing requires tumor tissue as well
as non-cancerous tissue as seen here; we've got the normal tissue and the tumor tissue,
which -- and normal tissue could be that from a surgical specimen or a blood sample. So
the tumor is classified as unstable when there are short repetitive sequences of the DNA
base in at least 30 percent of five or more markers analyzed. Here it's shown as repeats
of CA, CA, CA, or cytosine and adenosine, two of the four chemical bases that make up
DNA. MSI testing is also used in early stage colorectal cancer to guide choice of chemotherapy
since microsatellite-unstable tumors are resistant to 5-FU.
This is an example of an algorithm for evaluating a colorectal cancer case. Other algorithms
such as that updated yearly in the U.S. by the National Comprehensive Cancer Network,
the NCCN, are also available to guide genetic and genomic testing. And nowadays it's becoming
much more commonplace, at least in the United States, to initiate tumor testing for Lynch
syndrome with IHC and/or MSI at the time of initial diagnosis of a colon cancer. And in
a case where there is less suspicion of Lynch syndrome, for instance, some institutions
might be performing a BRAF testing when MLH1 is deficient on IHC, and the BRAF testing
can be used to rule out Lynch syndrome quickly and less costly than going to genetic testing
like sequencing. The common B600E mutation in BRAF is present is evidence of sporadic
versus hereditary colorectal cancer.
This here shows the DNA sequencing output for Mr. J. As we discussed, his tumor revealed
absence of the MLH1 protein, so the next step, then, is the targeted sequencing of the MLH1
gene. Here, this testing identified a DNA change at position 1975. You can see that
the normal sequence, CGA and arginine, was changed to TGA, so a thymine in place a cytosine,
resulting in what should have been the amino acid arginine being changed to a stop codon,
which terminates translation of the gene. This particular mutation is a well-known pathogenic
mutation in the United States, the United Kingdom, and Finland.
Here, this shows microarray, which is a means of looking at the DNA expression of multiple
genes simultaneously using a ChIP or other platform. Shown here we used fluorescent dyes
to identify gene expression. A commonly-used microarray in early stage breast and colon
cancers to help in deciding whether or not to undergo chemotherapy is the oncotype DX
test which gives a score of the likelihood of cancer recurrence. So a low score would
indicate a low chance of recurrence, and thus, that the individual would likely receive little
benefit from chemotherapy, whereas a high score would indicate a higher risk of recurrence
and a greater chemo benefit.
Turning to SNPs, or single-nucleotide polymorphisms, or that is relatively common changes found
in a population. Here we want to point out that four new SNPs associated with colorectal
cancer were identified via microarray analysis, which, when taken together with 10 previously-identified
SNPs, may account for about 6 percent of familial colorectal cancer. Other SNPs have been identified
that are associated with prognosis and morbidity. For example, SNPs have been found that are
associated with lymphedema in breast cancer. And this knowledge can help nurses to educate
women about means to reduce likelihood or severity of lymphedema.
Pharmacogenetics examines how genes influence drug actions including metabolism response,
and toxicity or side effects. For example, as much as 20 percent of drug metabolism has
been attributed to the P450 CYP2D6 enzyme, including response to tamoxifen and response
to the commonly-used antidepressants, trade names Prozac and Paxil, which are also sometimes
used to decrease hot flashes. So certain variants in CYP2D6 are associated with administered
response to these drugs, and thus, the benefit would be nil or suboptimal. Many SNPs have
been identified through GWAS, or genome-wide association studies, as was discussed by Dr.
Yvette Conley in the February 19th webinar.
Targeted therapy is another example of personalized medicine based on molecular features of a
patient's tumor. So drugs such as trastuzumab, trade name Herceptin, the first targeted medicine
which was approved by the United States Food and Drug Administration in 1998, are used
in human epidermal receptor 2, HER2-positive breast cancers to block cancer growth by binding
to the receptor site on the breast cancer cells. Since the advent of Herceptin, bone
marrow or stem cell transfer for breast cancer has pretty much become obsolete. Bevacizumab,
or Avastin, is another monoclonal antibody; it's used to inhibit the growth of new blood
vessels in several cancers.
This slide, which is in our article, shows how different drugs are used based on one's
genes, and how they influence drug response. So nurses could use this to explain to patients
who may wonder why they're not getting the same treatment as someone they know who has
the same cancer.
Back to Mr. J here, tumor testing per microsatellite instability helped guide the choice of chemotherapy,
and immunohistochemistry helped to determine the specific gene that was involved in his
developing colon cancer, and this provided very important information for the patient
in terms of his current care, as well as guiding future cancer surveillance for him since he
would need more frequent colonoscopy, as well as other tests for the Lynch syndrome associated
cancers, than would someone without this syndrome. And this also provided important information
for determining cancer risk in guiding screening and early detection strategies for his family,
as summed up in the next slide, including for his sister, his paternal aunt and her
adult children, and for his own daughter when she reaches adulthood and the age at which
she would be at risk and need to have strategies initiated if she carried the same mutation.
Okay, so, in conclusion, then, we have given you a glimpse into how genomics is changing
cancer care today, and, as such, informed nurses can educate and support patients in
how genetics and genomics impacts the continuum of cancer care, as well as risk management
and the treatment they receive. Table 2 in our article lists clinical resources to familiarize
and keep nurses up to date regarding genetics and genomics. And clearly, genetics and genomics
is changing the way cancer care is practiced, and nurses play a key role in helping patients
and families understand these new developments, and how they impact cancer and many other
areas of health care.
Thank you for listening to our presentation summarizing the article titled "Integration
of Genetics and Cancer Care" in the first quarter 2013 issue of the Journal of Nursing
Scholarship, dedicated to advances in genomics impacting cancer care and nursing practice.
We have a few minutes, I believe, before Dr. Seibert's presentation on caring for individuals
with genetic skin diseases to answer any questions.
Female Speaker: So I have opened the microphones for Dr. MacDonald
and Dr. Santos to be able to answer any questions that come up. Should you have a question,
please type them in.
"How important do you think that cancer genomics is for the care of cancer patients at this
point in time?" Either of you want to answer that?
Deborah MacDonald: Sure. Well, I think as we've shown, certainly
in breast cancer and in colon cancer, we didn't give any other examples, but in lung cancer,
melanoma, other cancers, we're beginning to use personalized care in genomics in guiding
the care, as we've shown, in how patients will respond to certain therapy so that we
could change the therapy if their genetic makeup shows that they don't respond to that
therapy, or in other ways such as that. Erika, did you want to add anything?
Erika Santos: No, I think that as we advance, we're going
to use this even more in our daily practice. So every time that we have a patient with
cancer, we're going to have this more and more. This is our daily -- we use this genetic
testing in a daily basis at least. And in my practice, I use this, and target therapy
is reality. Of course, that I live in Brazil, we still have some issues about covering issues
as -- covering as -- because target therapy is very expensive, and sometimes we have this
kind of problem. And also genetic testing is a problem, and sometimes because of insurance,
so we're having some debates here about that, but genetics and genomics is a reality, but
we're still discussing the coverage issues because it is very important thing to debate
also. So this debate is a ethic debate for us here also, so this is a problem.
Female Speaker: Thank you, Erika. The next question is, "How
can we get more education and training regarding SNP and the clinical utility?" And it says,
"Is testing available throughout the country, and what are the costs/insurance coverage
that's available?" And I think Erika addressed this for Brazil; Deborah, do you want to say
something about it for the United States?
Deborah MacDonald: Sure, sure. Well, there are certain tests
now that are covered by most of the insurers, and I think, you know that's -- as Erika said,
is evolving. And now we're looking at panels of testing, for instance, in families where
you may suspect there's a hereditary predisposition, but not due to the most common genes that
we typically test for, such as BRCA1 or BRCA2; there are now multigene panels that look at
several genes involved in the development of breast cancer.
Insurance coverage for those has -- is just beginning to come into play here with, I think,
that each individual case would probably need to be argued for at this point as to why that
might be necessary, and perhaps a more cost-effective approach than going through analyzing one
gene after the next, after the next. So we're on the forefront of all of this, and in terms
of learning more about it, I think it's just keeping up with the literature, going to formats
[spelled phonetically] such as the G3C case presentations that we are working on and have
several available already up on the website, www.g-3-c.org, and just keeping up with the
literature because this is a really evolving area; and speaking to your -- whoever is the
person in your area who may be more involved in this practice at the current time, an advanced
practice nurse working in genetics, or a genetic counselor, for instance.
Female Speaker: Well, thank you both very much for a very
informative talk, and just to reiterate, these talks are videotaped and audiotaped so they
will be recorded and archived on the genome.gov website, and at the end of Dr. Seibert's presentation,
the listing of the website, specifically on genome.gov, will be provided.
So I'm going to open up the microphone for Dr. Calzone to introduce Diane Seibert, and
as I change the presenter over to Diane, she'll be introduced. Thank you very much, Erika
and Deborah.
Kathleen Calzone: So, I'm delighted to introduce Dr. Diane Seibert.
Dr. Seibert is actually a practicing women's health nurse practitioner, and she's certified
in that capacity as well. Her current practice is at the Walter Reed National Military Medical
Center, formerly known as the National Naval Medical Center. She is a prolific writer,
and is professor and director of the Family Nurse Practitioner Program at the Uniformed
Services University of the Health Sciences here in Bethesda, Maryland. And so she is
going to talk to you about the genetics of skin disease.
Diane Seibert: Well, good afternoon everyone, I'm delighted
to be part of this group. It's been fun to listen to the talks over the last few weeks,
and I'm glad to be part of this little -- this edition for the Journal of Nursing Scholarship.
I am, as Kathy said, a women's health and adult nurse practitioner, so the genodermatoses,
the genetics of skin disease, wasn't something that I was all that familiar with until a
couple of years ago when I partnered with Tom Darling, my co-author, on this paper,
and he and I published an article in the Annals of Internal Medicine with an interesting population
of his over at NIH: women, adult women, with tuberous sclerosis who did not seem to have
the classic TSC triad of features of facial angiofibromas, seizure disorder, and mental
retardation. And those pictures on this particular slide show various features of this particular
skin -- inherited skin disease.
So I became -- I'm interested in this topic, and I realized I hadn't really read a whole
lot about the genodermatoses in the nursing literature, so I thought that I would like
to tackle this topic. So I'll take you with me on a journey as I kind of try to figure
out how to bring this topic to a larger audience.
So Physical, Psychological, & Ethical Issues in Caring for Individuals with Genetic Skin
Disease is what I decided to call this paper.
So just bit of background. The skin is, of course, the first line of defense between
our internal and external environments, and if you have healthy skin, it guards against
pathogen invasion, protects against water loss, it helps you regulate your temperature,
you feel sensations, it's part of our haptic sensation, in terms of balance, and it helps
us synthesis vitamins. There's been some really interesting work done related to maternal
Vitamin D exposure, and, for example, type 1 diabetes development in offspring. So some
very interesting things related to skin.
So genodermatoses, which, in fact, was a word I didn't really know anything -- I didn't
know that word existed until about a year ago, these are mutations that alter the way
normal skin works. Interestingly, and probably one of the things that Dr. Darling, my co-author,
said when I first approached him about helping me or co-authoring this paper with me, he
said, you know, genodermatoses are interesting in -- when you think of all genetic disease
in that this particular set of mutations don't normally shorten lifespan. There are some
of them that do, but most of them do not affect lifespan, but they have significant impacts
on social quality of life and social stigma because the skin is so visible to others.
And managing these disorders can be very complex. You first have to treat what's happening on
the skin. You have to educate the patients and their families about this disease, but
you also have to address the stigma, and, again, this is -- there's many places where
nurses play roles in this, if you think about all of these pieces and parts. You need to
treat and screen for the non-skin manifestations. As I said, you know, when I was talking about
tuberous psoriasis complex, it's the facial angiofibromas, which are the skin pieces,
but the seizure disorder and mental/cognitive impacts are significant for these diseases,
but recognize that there's lung tumors and also renal tumors as well. So the population
that Tom and I were working with at NIH that we wrote the paper on were adult women who
had very -- they had the disease, but it was not very expressive in them for whatever reason,
and they were -- they had transitioned into adulthood without a diagnosis, and many of
them had very severe pulmonary disease and were at high risk for lethal rupture of renal
tumors. So the recognition of the skin manifestations may lead you to a more -- potentially more
important diagnosis of some internal structural problem that you can help prevent that bad
outcome.
We also need to make appropriate referrals, and that can be complicated in these disorders
because, again, there are several variety of organ systems that may be involved so they
may require a team approach or several different referrals to different people.
When managing these diseases, roadblocks are pretty common. And until recently, deciding
what the actual diagnosis was was rather difficult. As we go into the talk a little bit farther,
you'll see -- I'll give highlights and examples of that. There were very few effective treatments
for some of these disorders. There wasn't much research, particularly in the rather
rare -- some of these rare recessive disorders, and, as a result -- and because they're rare
there are few other affected people in your community that you could talk to. And with
the advent of the Internet, that's changing pretty dramatically and helping this population
of patients, too.
So diagnosis of some of these rare conditions is now possible that we have gene sequencing
and we know what genes to look for. The Internet, as I kind of mentioned, people are able to
look outside their communities, local communities, for people that might also have these relatively
rare disorders, and the Internet is helping them find support groups. And here are several
that I ran in to as I was putting together this paper: Talk Against Genodermatoses, very
powerful and pretty robust site; psoriasis, albinism, incontinentia pigmenti, and an eczema
support group, so just an example. Lots of thing happening out there on the Internet
now.
So a little bit about the genetics. I was stunned, really, to realize that there are
over 500 genetic mutations that look like they cause somewhere in the neighbor of 560
or 570 distinct skin disorders, 400 of which can be traced to the specific gene. But it's
interesting because there is significant overlap between the disorders in terms of how they
manifest on the skin. So categorizing has rather been a nightmare. And if you go back
into history and look at textbooks of skin diseases, you'll find authors, you know, here's
a dry skin disorder, do we lump it with these other dry skin disorders. And so lots of confusion
in the community about what categorize -- you know, what category these disorders belong
in. But as we have come to better understand the physiology and pathophysiology of those
skin diseases, and the genetics of these diseases, they are settling on the genetic -- the dermatology
community has begun settling on classification systems. And there are about 12 of these categories
based on the type of skin lesion, and then they are further subdividing based on your
inheritance pattern.
Some of these disorders may surprise you. Osteogenesis Imperfecta: I think most of us
recognize of that as a fracture, boney fracture, but there are also skin manifestations with
that. Cowden syndrome is considered a cancer syndrome,
but there are skin features with that. Hypertriglyceridemia -- okay, that's cholesterol,
but skin shows up there. And hemochromatosis, iron overload. Again, there are skin features
for all these diseases. And so sometimes just highlighting or having clinicians recognize
the external manifestations gets you faster to a diagnosis for some of these.
Basically every inherence pattern is represented in the genodermatoses, but there are autosomal
dominant ones, recessive ones; there's X-linked, both dominant and recessive; there's mosaic.
There are complex conditions, lots of those where there's several genes plus an environmental
trigger, and then -- or a chronic environmental insult; and then there's significant heterogeneity
as well. Modifier genes are playing a role here for some of these, and it's certainly
environmental factors, exposure to sunlight, dry climates or humid climates, et cetera.
So the chapter is divided into -- you know, I was working with inherence patterns, and
here's the complex disorders. I started there because it was the most common things, atopic
dermatitis and psoriasis. So about 15 percent of kids living in industrialized countries
have atopic dermatitis. That's a pretty high number, and you realize that I put that word
"industrialized countries" in there. That's an environmental exposure that seems to be
triggering some of this skin disease. Symptoms: Most people usually have symptoms that manifest
in childhood and maybe make them absolutely miserable, hospitalized, et cetera, but many
of them -- many of these individuals get better as they age, so the skin seems to become a
little bit different with age.
The mutations appear to be largely centered in this filaggrin gene. There are four other
genes that they're working with as well. The mutation appears to cause an abnormal enzyme,
which prematurely disables these corneodesmosomes, and that causes an impaired barrier skin.
So things like irritants, soap, detergents, et cetera, damage this fragile skin; it's
not built very well. The allergens can get in, and then you have this inflammatory cascade.
So atopic dermatitis really is a model for the gene environment interaction and highlights
the differences in the expressivity because not all severely affected people have this
FLG mutations, and not all people with FLG mutations develop eczema. So -- and then this
whole idea that the older you get, the less disease you have is an interesting, complex
process, too.
The next one I thought I'd talk about is psoriasis. About up to 10 percent of people worldwide,
and that you notice there is no industrial piece in here. So it seems that there less
of a role -- industrialized communities or chemicals perhaps playing a role here. This
is an autoimmune T-cell disorder. There's an environmental trigger and a genetic susceptibility,
so both of these two pieces have to be present. The symptoms vary widely between people. And
it's different then the atopic dermatitis in that in psoriasis, there's a very rapid
skin maturation, so the skin cells don't have this have nice-paced growth. They accelerate
the growth rapidly. The cells pile up on top of each other. That -- the immune system's
not happy with that big callus-type formation, and so the immune system comes in to clean
that up. So when you have very severe psoriasis, and many of you may have seen patients with
really -- it's on the, sort of the external surface areas, atopic dermatitis tends to
be in folds and bends, and psoriasis tends to be on external -- the outsides of elbows
and knees and that kind of stuff. And it's a severe disease. They've done some studies
to show that quality of life scores for these patients are similar to that of patients with
other chronic diseases like hypertension, and depression, and CHF, and type 2 diabetes.
So this can be a very debilitating disease.
There's candidate genes, but recognize that these genes are not necessarily skin genes.
These are immune genes, like that you'll find in the HLA complex of genes, particularly
-- this particular one HLA-Cw0602. And then interleukin genes seem to be involved. These
guys are also involved in immune modulation. So this is an immune mutation disorder. Interesting.
So here are some of the monogenic, or single gene, disorders that I thought were prevalent
enough and interesting enough that you might, a) see them, or b) kind of be interested,
or they're markers for model disorders, I guess, for other skin diseases.
So the autosomal dominant I thought I'd talk about is Peutz-Jeghers. Then in recessive,
we'll talk about albinism. And then we'll talk about one X-linked disorder, incontinentia
pigmenti.
So Peutz-Jeghers, or PJS, is an autosomal-dominant cancer syndrome. That picture up there shows
you some of the skin findings inside someone's mouth. It's the STK and LKB1 tumor suppressor
gene. If that gene is broken, they're life -- this individual's lifetime risk for developing
cancers is very, very high, 93 percent. In childhood, these individuals often have skin
lesions, these dark blue or brawn macules on fingers, faces, perianal areas. If you
see these in any of your patients in childhood, you need to begin cancer screening, or you
should at least consider this Peutz-Jeghers diagnose.
It also comes -- because it is a cancer syndrome, this is a tumor suppressor gene that is broken,
you'll see some other manifestations: hamartomatous gastrointestinal polyps, stomach, small intestine,
large bowel, nasal passages. Although these are rarely cancerous, they do get large and
they do bleed, so anemia is a possibility, as well as bowel obstruction and intussusceptions
in young -- usually in younger children. And then epithelial cancers: colorectal, gastric,
pancreatic, breast, and ovarian. So this is a pretty serious mutation and -- if the skin
can be the first thing that someone recognizes and starts early screening and intervention,
you may have really gone a long way to improve someone's overall survival and quality of
life.
The genetics are -- as I mentioned, it was in this STK11 and LKB1 genes, but the -- still
not really clear how this genetics all works with Peutz-Jeghers because there are a number
of de novo mutations, and it appears to also be heterogenic where multiple genes are involved
so not everyone has the same genetic -- they look phenotypically the same, but they don't
have the same genetic picture. So when you find somebody who has the clinical features,
you counsel as you would for other autosomal dominant disorders and tell the family that
the inheritance risk is about 50 percent. And that if the mutation is known, prenatal
testing is available for Peutz-Jeghers.
Albinism. It's an autosomal recessive disorder, and it involves melanin defects, either the
synthesis and/or the transport of melanin into the skin. The incidence around the world
is about 1 in 17,000 individuals, but there's some pockets around the globe where the incidence
is much higher than that. In Sub-Saharan Africa, 1 in 4,000 Zimbabweans, and almost 1 in 1,400
Tanzanians. So these communities have a lot of consanguinity, a lot of intermarriages
or even close marriages across neighboring communities, and maybe not very much awareness
of how this is actually inherited. The most prevalent form is this Oculocutaneous albinism,
or OCA, and there's four subtypes. And it depends on how -- what the mutations are like,
and if they're completely broken and make no melanin at all, or whether they produce
still a little bit of melanin really kind of drives how this patient is going to appear
externally and how many manifestations they're going to have, because melanin is -- interesting
-- is critical not only for the skin color, but it is also important for eye development.
Obviously, you can see the picture on the top right, a lot of solar damage.
So skin cancer is very common in this population. And the eye -- it's not only just the fact
that there's no pigment in the eye, but also eye muscles. So they have poor eye movement,
poor visual acuity, and these children also then have difficulty reading and school challenges.
They not only look different now, they actually have some intellectual -- not cognitively
challenged, but acquiring information is difficult. They have, again, high prevalence of skin
cancer. And that -- in this culture, in the United States, it may not be so unusual to
see little kids at the beach wearing the long-sleeved things now, they're starting to do a lot of
that, but in Sub-Saharan Africa, it would pretty unusual, and probably these people
would be a bit shunned if they start wearing long sleeves and hats, things they need to
do to protect their skin.
So social stigma for these children, in particular, can be very profound. They have very pale
skin, pink eyes, they struggle in school, they often stay inside, they wear unusual
clothing. And this is an extreme example of the social stigma, but in some South African
albino communities, there are body hunters that are actually look for albino people.
They kill them or they dismember them and make their body parts into good luck charms.
So very scary. These communities, there are children that actually flee to the quote,
unquote "safety" of larger, anonymous urban communities trying to stay alive, basically,
which increases their isolation and their marginalization. So this is a big problem.
And so, again, this skin mutation, if you can protect their skin and help them with
their learning needs, it doesn't really affect longevity. But if the social stigma is so
severe that they have to find themselves in a lonely community, isolated, it can be a
very debilitating disease.
Incontinentia pigmenti is a very rare disorder. It's X-linked dominant. What's interesting
about this I really learned more about X-linked -- most of the X-linked disorders that I had
really thought about before were really recessive disorders. This is one is dominant. So if
you have one mutation, you're affected. And so that means that girls are affected. If
you are a male and you only have one X, and that one happens to be affected, you usually
don't get out of embryogenesis. Or if you make it to term pregnancy, you often die very
early in your life. So the people affected by incontinentia pigmenti are women. There's
only about 700 women around the world; that's because it is lethal in virtually all men,
you're not going to see it in boys. The diagnosis is interesting because, again, it's a clinical
diagnosis confirmed by skin biopsy, or now by gene testing. And the expression varies
really widely.
They have this very interesting development of skin lesion from birth into adulthood.
They have this very severe blistering, and that's -- this picture that I put up here
doesn't really represent some of the pictures. If you go to Google Images and do a search
on this, you'll see some severe skin manifestations. But blistering until about four months of
age, then this wart-like rash that appears for several months. Then they have hyperpigmentation
for the rest of their lives, and they have this very interesting brown and slate-gray
lines, wavy lines, and again, you'll see some of those if you do a Google search on it.
And then they also have very interesting features like the alopecia, the strange teeth, formation
of teeth, dystrophic nails, cataracts, so, again, more eye features, retinal detachment,
severe vision loss. Again, cognitive delay and intellectual disability. And then some
very, potentially, really severe skeletal abnormalities: hemivertebrae, scoliosis, spina
bifida, syndactyly, and a congenital absence of the hands, all of which caused by a X-linked
mutation.
So what's the role of nursing? Hopefully as I went through of this, kind of, again, quickly,
you could think of ways in which you might interact with some of these patients. We are
basically everywhere in health care. We're engaged with people in virtually every life
event from birth to death to every place in between. We're present in all health care
settings, we work with all populations, and the public expects us to understand how genetic
conditions are inherited. Again, those communities in Africa that need more education about albinism.
They need -- they expect us to understand how common conditions are inherited including
things like skin diseases, like atopic dermatitis. They want us to help them navigate some of
the social and ethical issues, recognizing that children with albinism have visual challenges
as well, and helping them access those resources. Just understanding the relationship between
the eyes and social outcomes is important.
They also expect us to help them navigate some of these physical, and emotional, and
social consequences of some of the disorders that they have. They want us to help them
get access to some reputable resources. There's a lot of stuff on the Internet. And, again,
as I was searching around looking for things to bring to you, you run into interesting
and very unhelpful or misleading pieces of information. They want this stuff rapidly,
so that you're being facile with the computer really helps your patients. And then offering
suggestions about coping, how to cope with some of the funny looks, or the fact that
no one will shake your hand, or laugh at the way that your hair or eyes are colored, et
cetera.
So our job, in terms of preparing nurses, my job here at the university is to be aware
of what it is that nurses need to know. And I think, hopefully, all of you are familiar
with the two guidelines now that have been published related to what all nurses need
to know. The Essentials of Genetic and Genomic Nursing: Competencies with the Outcome Indicators
from 2008. And then the new Essential Genetic and Genomic Competencies for Nurses Prepared
at the Graduate Level that was published last year.
So, in conclusion, really, nurses need to be familiar with the genodermatoses more commonly
seen in your communities; need to be prepared to develop individualized care plans for patients
and families with genetic concerns; and be able to discussed the ethical issues that
surround genetic testing which includes incidental findings. There's been some new work, ACMG
released a new paper recently about how to -- an approach, at least, incidental findings.
So skin diseases affect millions around the world. It's accompanied by significant morbidity,
which includes quality of life issues, social stigma, isolation. We're still learning about
the genodermatoses. Many people don't understand them very well. The ethical, legal, and social
implications are similar to those patients that have other genetic diseases, including
all the issues around genetic testing. And nurses are important because we can link the
science of genetics with the human experience of health and illness. And we can make an
important, positive difference in the lives of our patients, of all of our patients, but
in this context, in patients with hereditary skin disease.
So I think I will stop there and see if there are any questions or comments. Hopefully,
I can answer some. Like I said, I'm not a particular expert in this.
Female Speaker: So, Diane, there was a question from an attendee
who says, "I had a patient with sclerosed fibroma of the nose. The dermatologist recommended
P10 testing. Is this lesion part of the P10 spectrum?"
Diane Seibert: That is a good question, and I don't have
a good answer for that. I would have to -- I'd have to do a literature search to find that
answer myself. I don't know if Deborah or Erika, or either you or Kathy have an answer
for that.
Female Speaker: So I've opened up the microphone. Does anybody
else want to address the P10 discussion about the fibrosis [spelled phonetically] of the
nose?
Female Speaker: What was it in the nose? I didn't quite get
it.
Female Speaker: Maybe you didn't [spelled phonetically]. It
says, "Fibroma -- a sclerosed fibrosis of nose, and the dermatologist recommended P10
testing. Is this lesion part of the P10 spectrum?"
Female Speaker: Well, there are sclerotic fibromas that can
be seen in Cowden syndrome, so it could be a cutaneous marker of the disease. I've not
come across it myself so I'd have to do a little more -- I'd have to look it up a bit
and see if it actually meets criteria for testing, but it is a marker of -- that has
been found in Cowden's disease before. So...
Female Speaker: Dr. Calzone, do you want to tell them a little
bit about the PDQ database where some of this information might be located?
Kathleen Calzone: So pdq@cancer.gov actually maintains evidence-based
reviews of Hereditary Cancer Syndromes and other associated variables. If you go to cancer.gov,
you can look at an individual topic, and in Cowden's, for example, it falls under the
genetics of breast and ovarian cancer because it's a syndrome that is associated with breast
cancer as well as other cancers. And when you click on breast cancer at cancer.gov,
you just scroll down to the genetics section, and there will be a whole section on the current
evidence associated with Cowden's, and the clinical criteria associated with the, you
know, indications for testing for mutations in P10.
Female Speaker: Thank you. Any other questions that people
want to submit, go ahead and do so.
And Diane, could you move to the next slide which also shoes the next webinar coming up
if you have that available.
So while we wait for the last few questions, just a reminder that the next webinar is April
26, and it will be on autism, as well as an update of childhood genetic disorders. So
if you have colleagues that are interested in pediatric conditions, please tell them
about how to register for this webinar for April 26.
So I don't see any other questions, so I'm going to up the microphones to our presenters
just to have one last word before we close out of the day. Deborah, any other parting
comments?
Deborah MacDonald: Well, actually I do have a question. Diane,
that was excellent presentation. Thank you so much, and I certainly learned a lot. I
have a question about Peutz-Jeghers testing. I think you mentioned that there was prenatal
testing available. And how would this be useful, or is there some intervention that would be
initiated that would justify prenatal testing, or is this something where people might even
chose to terminate?
Diane Seibert: Well, that's a really good question. I think
that that comes up with a lot of -- the more we know about genetics, the more tempting
it is to do things preconceptually or conceptually. So if you know what the family mutation is,
of course you can screen for it. You could do it pregestationally, with a PGD, Pregestational
Diagnostic Testing, or you could test for it prenatally. That's a discussion that, again,
these patients should -- in my view, these conversations should occur prior to conception,
certainly. Like, what are you going to do with this information? But the fact is that
it does exist, and so hopefully you're not first diagnosing something like a cancer syndrome
in -- early in pregnancy, and have to then make a decision about whether you're going
to do prenatal testing. Ideally you do that before you ever got pregnant. And it's going
to raise a lot of issues over the next decade or so if the cell-free DNA even increases,
potentially increases the sensitivity, decreasing the risk for normal fetuses, too.
Female Speaker: Erika, any last comment?
Erika Santos: No. I would like to say thank you, too [spelled
phonetically], that was a very good presentation, and I'd like to say thank you for the opportunity
Female Speaker: Well, thank you for joining us from Brazil.
And I now that is very difficult to make sure all these connections work, so thank you.
And Kathy, any last comments?
Kathleen Calzone: No, none here. We hope that you'll join us
in -- for the next set of webinars that's coming up at the end of the month.
Female Speaker: So thank you Diane, and Deborah, and Erika.
Any other comment, Diane?
Diane Seibert: No, I don't think so. I enjoyed it. Thank
you. I think it was a very good pairing of these two talks together. I appreciated the
-- I really learned a lot from the cancer one, too. So thank you.
Female Speaker: Thank you very much.
Deborah MacDonald: This is Deborah. So I'd just like to say,
you know, I think the bit -- we're in a very rapidly developing era that is changing health
care quite dramatically and will continue to do so, so that webinars and publications,
such as in the Journal of Nursing Scholarship, are really necessary for nurses to be kept
current about what's going on in these arenas, and to be able to not only use this information
with their own patients and families, but also even with others health care providers,
including clinicians and others, who may not be aware of the latest developments.
Female Speaker: Well, thank you all --
[end of transcript]