Integration of Genomics in Cancer Care & Issues in Caring for Individuals with Genetic Skin Disease

Integration of Genomics in Cancer Care & Issues in Caring for Individuals with Genetic Skin Disease


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 [email protected] 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 to discuss this with you. So thank you all. 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]

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