Colon Cancer Polyp

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 ustoday. and the first is dr. erika santos, and she's actually joining us from sã£o paulo,brazil, and is currently working at the hospital a.c. camargo in their oncology and hereditarycolorectal cancer program there. and in addition to that facility, she is also the supervisorfor their graduate program, and she teaches oncology nursing. erika is very active inthe international society of nurses in genetics and is the editor of the newsletter, and she'sbeen the editor for several years now.

and then dr. deborah macdonald is also joiningus, she'll speak second in this particular presentation. and since january, deborah'sbeen working with me here at the national cancer institute and the center for cancerresearch in the genetics branch. prior to that, she's had an illustrious career in cancergenetics, first at massachusetts general hospital, and then for many years now at the city ofhope comprehensive cancer center in their clinical cancer genetics program that shehelped develop there with the team. she's been a longstanding member of isong and wasa former president of the international society of nurses in genetics. so i'm going to turnit 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 20minutes about integration of genomics in cancer care. on behalf of all the authors in thispaper, we would like to thank nih for this opportunity to talk about -- with you aboutthis issue. next, please. next slide. so the aim is to introduce how genetics andgenomics 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 targetedcancer 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 cancerand 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 of41 and two polyps. his father had colon cancer at the age of 41 -- 50. his father had -- hisaunt had uterine cancer at the age of 43, and his grandmother had colon cancer at theage of 52. so we will discuss this -- the implication of his personal cancer historyand his familial cancer history later on. but first of all, i would like to talk withyou about the etiology of cancer, and cancer as a genetic disease. next. so cancer is agenetic disease, is multifactorial, and infection and chemical products and radiation altersdna 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 thatare related to the cancer development because this is important for cancer risk assessment. so there are different risk factors that arerelated to the cancer development, and nurses must recognize those risk factors. and theradiation, chemical, and biological, and one of the important risk factors are geneticsusceptibility. next. so if we -- according to cancer history, familyhistory, tumors can be classified as sporadic, familial, and hereditary. this has very importantimplications for the development or the strategies for monitoring individuals and also at-riskfamily members. next. sporadic tumors account for 75 percent of all cancers, and usuallyoccurs at an age of onset that is expected

for this -- the kind of cancer that we aretalking about. for example, colon cancer at age of 65. they are related to somatic mutationsin a specific tissue, for example, breast or colon cancer [unintelligible]. next. on the other hand, if -- sometimes we cansee the same type of cancer occurring at the expect age but in more than one close relativeon the same side of the family; for example, two siblings with colon cancer after the ageof 60, or two sisters with breast cancer with age of 65, and sometimes this is referredas familial cancer. these account for 10 to 15 percent of all cancers. and this is likelythe 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 todeveloping certain cancers. the hallmark is an early age at onset that normally wouldnot [spelled phonetically] be expected for a particular cancer, for example, colon cancerat age of 30, or breast cancer age of 30. and this is, as i said, a germline mutationthat is usually related to this kind of cancer. next. so most germline mutation are transmittedto 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 differenceamong acquired, inheritable genetic mutation? this is very important because it is a keyto 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 thisis 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 geneticand 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 implicationsfor cancer risk assessment. and the -- one

of the most important thing is, is to provideeducation, 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 weneed to identify those individuals who should benefit with this strategy. so we have thered flags; so red flags are features on personal or family history of cancer that draw attentionto suspect familial or hereditary cancer. so these are the red flags; they're only anindication 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, breastand 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 mutationin 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 cancheck some red flags here. so we have age at diagnosis, earlier than expected. morethan colon cancer -- three cases of colon cancer, which is not expected here, so, wehave three cases of colon cancer. and we have also a constellation syndrome, which is uterinecancer 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 ofgenomic 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 arefactors that can change the expression of the gene or the physical, physiologic, orbiochemical characteristics of an individual that are not due to a change in the dna. so here we take our example of tumor profilingby a process known as immunohistochemistry, or ihc. in mr. j's case, this test is performedin the pathology lab on tumor tissue to screen

for lynch syndrome by examining the proteinexpression 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 comparedto 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 thantesting for all four genes, and thus it's a more effective and a less costly strategy. so microsatellite instability testing, ormsi, is another laboratory test that when microsatellite instability is found, it suggeststhat the individual has lynch syndrome. however, about 10 to 15 percent of microsatellite instabilityis present in various sporadic cancers, so

this is a clue, as is ihc, that there couldbe 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'vegot the normal tissue and the tumor tissue, which -- and normal tissue could be that froma surgical specimen or a blood sample. so the tumor is classified as unstable when thereare short repetitive sequences of the dna base in at least 30 percent of five or moremarkers 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 stagecolorectal cancer to guide choice of chemotherapy since microsatellite-unstable tumors are resistantto 5-fu.

this is an example of an algorithm for evaluatinga colorectal cancer case. other algorithms such as that updated yearly in the u.s. bythe national comprehensive cancer network, the nccn, are also available to guide geneticand genomic testing. and nowadays it's becoming much more commonplace, at least in the unitedstates, to initiate tumor testing for lynch syndrome with ihc and/or msi at the time ofinitial diagnosis of a colon cancer. and in a case where there is less suspicion of lynchsyndrome, for instance, some institutions might be performing a braf testing when mlh1is deficient on ihc, and the braf testing can be used to rule out lynch syndrome quicklyand less costly than going to genetic testing like sequencing. the common b600e mutationin braf is present is evidence of sporadic

versus hereditary colorectal cancer. this here shows the dna sequencing outputfor 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 dnachange at position 1975. you can see that the normal sequence, cga and arginine, waschanged to tga, so a thymine in place a cytosine, resulting in what should have been the aminoacid 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 unitedkingdom, and finland. here, this shows microarray, which is a meansof looking at the dna expression of multiple

genes simultaneously using a chip or otherplatform. shown here we used fluorescent dyes to identify gene expression. a commonly-usedmicroarray in early stage breast and colon cancers to help in deciding whether or notto undergo chemotherapy is the oncotype dx test which gives a score of the likelihoodof 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 highscore 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 outthat 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 familialcolorectal 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 orseverity of lymphedema. pharmacogenetics examines how genes influencedrug 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, tradenames prozac and paxil, which are also sometimes

used to decrease hot flashes. so certain variantsin cyp2d6 are associated with administered response to these drugs, and thus, the benefitwould be nil or suboptimal. many snps have been identified through gwas, or genome-wideassociation studies, as was discussed by dr. yvette conley in the february 19th webinar. targeted therapy is another example of personalizedmedicine 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 foodand drug administration in 1998, are used in human epidermal receptor 2, her2-positivebreast cancers to block cancer growth by binding to the receptor site on the breast cancercells. since the advent of herceptin, bone

marrow or stem cell transfer for breast cancerhas 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, showshow 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 thesame treatment as someone they know who has the same cancer. back to mr. j here, tumor testing per microsatelliteinstability helped guide the choice of chemotherapy, and immunohistochemistry helped to determinethe specific gene that was involved in his

developing colon cancer, and this providedvery important information for the patient in terms of his current care, as well as guidingfuture cancer surveillance for him since he would need more frequent colonoscopy, as wellas 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 screeningand early detection strategies for his family, as summed up in the next slide, includingfor his sister, his paternal aunt and her adult children, and for his own daughter whenshe reaches adulthood and the age at which she would be at risk and need to have strategiesinitiated if she carried the same mutation. okay, so, in conclusion, then, we have givenyou a glimpse into how genomics is changing

cancer care today, and, as such, informednurses can educate and support patients in how genetics and genomics impacts the continuumof cancer care, as well as risk management and the treatment they receive. table 2 inour article lists clinical resources to familiarize and keep nurses up to date regarding geneticsand 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 presentationsummarizing the article titled "integration of genetics and cancer care" in the firstquarter 2013 issue of the journal of nursing

scholarship, dedicated to advances in genomicsimpacting 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 questionsthat come up. should you have a question, please type them in. "how important do you think that cancer genomicsis for the care of cancer patients at this point in time?" either of you want to answerthat? deborah macdonald:sure. well, i think as we've shown, certainly

in breast cancer and in colon cancer, we didn'tgive any other examples, but in lung cancer, melanoma, other cancers, we're beginning touse personalized care in genomics in guiding the care, as we've shown, in how patientswill respond to certain therapy so that we could change the therapy if their geneticmakeup 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 andmore. this is our daily -- we use this genetic testing in a daily basis at least. and inmy 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 therapyis very expensive, and sometimes we have this kind of problem. and also genetic testingis 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 issuesbecause it is very important thing to debate also. so this debate is a ethic debate forus here also, so this is a problem. female speaker:thank you, erika. the next question is, "how can we get more education and training regardingsnp 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 addressedthis 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 panelsof 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 developmentof breast cancer. insurance coverage for those has -- is justbeginning to come into play here with, i think,

that each individual case would probably needto be argued for at this point as to why that might be necessary, and perhaps a more cost-effectiveapproach than going through analyzing one gene after the next, after the next. so we'reon the forefront of all of this, and in terms of learning more about it, i think it's justkeeping up with the literature, going to formats [spelled phonetically] such as the g3c casepresentations 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 evolvingarea; and speaking to your -- whoever is the person in your area who may be more involvedin this practice at the current time, an advanced practice nurse working in genetics, or a geneticcounselor, for instance.

female speaker:well, thank you both very much for a very informative talk, and just to reiterate, thesetalks are videotaped and audiotaped so they will be recorded and archived on the genome.govwebsite, and at the end of dr. seibert's presentation, the listing of the website, specifically ongenome.gov, will be provided. so i'm going to open up the microphone fordr. calzone to introduce diane seibert, and as i change the presenter over to diane, she'llbe 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'shealth nurse practitioner, and she's certified

in that capacity as well. her current practiceis at the walter reed national military medical center, formerly known as the national navalmedical center. she is a prolific writer, and is professor and director of the familynurse practitioner program at the uniformed services university of the health scienceshere in bethesda, maryland. and so she is going to talk to you about the genetics ofskin disease. diane seibert:well, good afternoon everyone, i'm delighted to be part of this group. it's been fun tolisten to the talks over the last few weeks, and i'm glad to be part of this little -- thisedition for the journal of nursing scholarship. i am, as kathy said, a women's health andadult nurse practitioner, so the genodermatoses,

the genetics of skin disease, wasn't somethingthat i was all that familiar with until a couple of years ago when i partnered withtom darling, my co-author, on this paper, and he and i published an article in the annalsof internal medicine with an interesting population of his over at nih: women, adult women, withtuberous sclerosis who did not seem to have the classic tsc triad of features of facialangiofibromas, seizure disorder, and mental retardation. and those pictures on this particularslide 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 nursingliterature, so i thought that i would like

to tackle this topic. so i'll take you withme on a journey as i kind of try to figure out how to bring this topic to a larger audience. so physical, psychological, & ethical issuesin caring for individuals with genetic skin disease is what i decided to call this paper. so just bit of background. the skin is, ofcourse, the first line of defense between our internal and external environments, andif you have healthy skin, it guards against pathogen invasion, protects against waterloss, it helps you regulate your temperature, you feel sensations, it's part of our hapticsensation, in terms of balance, and it helps us synthesis vitamins. there's been some reallyinteresting work done related to maternal

vitamin d exposure, and, for example, type1 diabetes development in offspring. so some very interesting things related to skin. so genodermatoses, which, in fact, was a wordi didn't really know anything -- i didn't know that word existed until about a yearago, these are mutations that alter the way normal skin works. interestingly, and probablyone of the things that dr. darling, my co-author, said when i first approached him about helpingme or co-authoring this paper with me, he said, you know, genodermatoses are interestingin -- when you think of all genetic disease in that this particular set of mutations don'tnormally shorten lifespan. there are some of them that do, but most of them do not affectlifespan, but they have significant impacts

on social quality of life and social stigmabecause 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 patientsand 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 aboutall 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 facialangiofibromas, which are the skin pieces, but the seizure disorder and mental/cognitiveimpacts are significant for these diseases, but recognize that there's lung tumors andalso renal tumors as well. so the population

that tom and i were working with at nih thatwe wrote the paper on were adult women who had very -- they had the disease, but it wasnot very expressive in them for whatever reason, and they were -- they had transitioned intoadulthood without a diagnosis, and many of them had very severe pulmonary disease andwere at high risk for lethal rupture of renal tumors. so the recognition of the skin manifestationsmay lead you to a more -- potentially more important diagnosis of some internal structuralproblem 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 varietyof organ systems that may be involved so they

may require a team approach or several differentreferrals to different people. when managing these diseases, roadblocks arepretty 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 examplesof that. there were very few effective treatments for some of these disorders. there wasn'tmuch 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 yourcommunity that you could talk to. and with the advent of the internet, that's changingpretty dramatically and helping this population of patients, too.

so diagnosis of some of these rare conditionsis 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 helpingthem find support groups. and here are several that i ran in to as i was putting togetherthis paper: talk against genodermatoses, very powerful and pretty robust site; psoriasis,albinism, incontinentia pigmenti, and an eczema support group, so just an example. lots ofthing happening out there on the internet now. so a little bit about the genetics. i wasstunned, really, to realize that there are

over 500 genetic mutations that look likethey cause somewhere in the neighbor of 560 or 570 distinct skin disorders, 400 of whichcan be traced to the specific gene. but it's interesting because there is significant overlapbetween the disorders in terms of how they manifest on the skin. so categorizing hasrather been a nightmare. and if you go back into history and look at textbooks of skindiseases, you'll find authors, you know, here's a dry skin disorder, do we lump it with theseother dry skin disorders. and so lots of confusion in the community about what categorize -- youknow, what category these disorders belong in. but as we have come to better understandthe 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 classificationsystems. and there are about 12 of these categories based on the type of skin lesion, and thenthey 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 justhighlighting or having clinicians recognize

the external manifestations gets you fasterto a diagnosis for some of these. basically every inherence pattern is representedin 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 thosewhere there's several genes plus an environmental trigger, and then -- or a chronic environmentalinsult; and then there's significant heterogeneity as well. modifier genes are playing a rolehere 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 therebecause it was the most common things, atopic

dermatitis and psoriasis. so about 15 percentof kids living in industrialized countries have atopic dermatitis. that's a pretty highnumber, and you realize that i put that word "industrialized countries" in there. that'san 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 absolutelymiserable, hospitalized, et cetera, but many of them -- many of these individuals get betteras they age, so the skin seems to become a little bit different with age. the mutations appear to be largely centeredin this filaggrin gene. there are four other genes that they're working with as well. themutation 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 getin, and then you have this inflammatory cascade. so atopic dermatitis really is a model forthe gene environment interaction and highlights the differences in the expressivity becausenot all severely affected people have this flg mutations, and not all people with flgmutations develop eczema. so -- and then this whole idea that the older you get, the lessdisease 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 industrialpiece in here. so it seems that there less of a role -- industrialized communities orchemicals perhaps playing a role here. this is an autoimmune t-cell disorder. there'san 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 dermatitisin that in psoriasis, there's a very rapid skin maturation, so the skin cells don't havethis have nice-paced growth. they accelerate the growth rapidly. the cells pile up on topof 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 externalsurface areas, atopic dermatitis tends to be in folds and bends, and psoriasis tendsto be on external -- the outsides of elbows and knees and that kind of stuff. and it'sa severe disease. they've done some studies to show that quality of life scores for thesepatients 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 thatthese genes are not necessarily skin genes. these are immune genes, like that you'll findin the hla complex of genes, particularly -- this particular one hla-cw0602. and theninterleukin 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 singlegene, 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, iguess, for other skin diseases. so the autosomal dominant i thought i'd talkabout is peutz-jeghers. then in recessive, we'll talk about albinism. and then we'lltalk about one x-linked disorder, incontinentia pigmenti. so peutz-jeghers, or pjs, is an autosomal-dominantcancer syndrome. that picture up there shows you some of the skin findings inside someone'smouth. 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. inchildhood, these individuals often have skin lesions, these dark blue or brawn maculeson 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-jeghersdiagnose. it also comes -- because it is a cancer syndrome,this is a tumor suppressor gene that is broken, you'll see some other manifestations: hamartomatousgastrointestinal polyps, stomach, small intestine, large bowel, nasal passages. although theseare 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. andthen epithelial cancers: colorectal, gastric, pancreatic, breast, and ovarian. so this isa pretty serious mutation and -- if the skin can be the first thing that someone recognizesand starts early screening and intervention, you may have really gone a long way to improvesomeone's overall survival and quality of life. the genetics are -- as i mentioned, it wasin this stk11 and lkb1 genes, but the -- still not really clear how this genetics all workswith peutz-jeghers because there are a number of de novo mutations, and it appears to alsobe heterogenic where multiple genes are involved so not everyone has the same genetic -- theylook phenotypically the same, but they don't

have the same genetic picture. so when youfind somebody who has the clinical features, you counsel as you would for other autosomaldominant 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 melanininto the skin. the incidence around the world is about 1 in 17,000 individuals, but there'ssome 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 lotof consanguinity, a lot of intermarriages

or even close marriages across neighboringcommunities, and maybe not very much awareness of how this is actually inherited. the mostprevalent form is this oculocutaneous albinism, or oca, and there's four subtypes. and itdepends on how -- what the mutations are like, and if they're completely broken and makeno melanin at all, or whether they produce still a little bit of melanin really kindof drives how this patient is going to appear externally and how many manifestations they'regoing 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 thetop 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 alsoeye muscles. so they have poor eye movement, poor visual acuity, and these children alsothen have difficulty reading and school challenges. they not only look different now, they actuallyhave some intellectual -- not cognitively challenged, but acquiring information is difficult.they have, again, high prevalence of skin cancer. and that -- in this culture, in theunited states, it may not be so unusual to see little kids at the beach wearing the long-sleevedthings now, they're starting to do a lot of that, but in sub-saharan africa, it wouldpretty unusual, and probably these people would be a bit shunned if they start wearinglong 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 ofthe social stigma, but in some south african albino communities, there are body huntersthat are actually look for albino people. they kill them or they dismember them andmake their body parts into good luck charms. so very scary. these communities, there arechildren that actually flee to the quote, unquote "safety" of larger, anonymous urbancommunities trying to stay alive, basically, which increases their isolation and theirmarginalization. so this is a big problem. and so, again, this skin mutation, if youcan protect their skin and help them with

their learning needs, it doesn't really affectlongevity. but if the social stigma is so severe that they have to find themselves ina 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 recessivedisorders. this is one is dominant. so if you have one mutation, you're affected. andso that means that girls are affected. if you are a male and you only have one x, andthat one happens to be affected, you usually don't get out of embryogenesis. or if youmake it to term pregnancy, you often die very

early in your life. so the people affectedby incontinentia pigmenti are women. there's only about 700 women around the world; that'sbecause it is lethal in virtually all men, you're not going to see it in boys. the diagnosisis interesting because, again, it's a clinical diagnosis confirmed by skin biopsy, or nowby gene testing. and the expression varies really widely. they have this very interesting developmentof skin lesion from birth into adulthood. they have this very severe blistering, andthat'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 appearsfor several months. then they have hyperpigmentation for the rest of their lives, and they havethis very interesting brown and slate-gray lines, wavy lines, and again, you'll see someof those if you do a google search on it. and then they also have very interesting featureslike the alopecia, the strange teeth, formation of teeth, dystrophic nails, cataracts, so,again, more eye features, retinal detachment, severe vision loss. again, cognitive delayand intellectual disability. and then some very, potentially, really severe skeletalabnormalities: hemivertebrae, scoliosis, spina bifida, syndactyly, and a congenital absenceof the hands, all of which caused by a x-linked mutation.

so what's the role of nursing? hopefully asi went through of this, kind of, again, quickly, you could think of ways in which you mightinteract with some of these patients. we are basically everywhere in health care. we'reengaged with people in virtually every life event from birth to death to every place inbetween. we're present in all health care settings, we work with all populations, andthe public expects us to understand how genetic conditions are inherited. again, those communitiesin africa that need more education about albinism. they need -- they expect us to understandhow 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, recognizingthat 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 navigatesome of these physical, and emotional, and social consequences of some of the disordersthat they have. they want us to help them get access to some reputable resources. there'sa lot of stuff on the internet. and, again, as i was searching around looking for thingsto bring to you, you run into interesting and very unhelpful or misleading pieces ofinformation. they want this stuff rapidly, so that you're being facile with the computerreally helps your patients. and then offering suggestions about coping, how to cope withsome of the funny looks, or the fact that

no one will shake your hand, or laugh at theway 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. andi think, hopefully, all of you are familiar with the two guidelines now that have beenpublished related to what all nurses need to know. the essentials of genetic and genomicnursing: competencies with the outcome indicators from 2008. and then the new essential geneticand genomic competencies for nurses prepared at the graduate level that was published lastyear. so, in conclusion, really, nurses need tobe familiar with the genodermatoses more commonly

seen in your communities; need to be preparedto develop individualized care plans for patients and families with genetic concerns; and beable to discussed the ethical issues that surround genetic testing which includes incidentalfindings. 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 theworld. it's accompanied by significant morbidity, which includes quality of life issues, socialstigma, isolation. we're still learning about the genodermatoses. many people don't understandthem very well. the ethical, legal, and social implications are similar to those patientsthat have other genetic diseases, including all the issues around genetic testing. andnurses are important because we can link the

science of genetics with the human experienceof health and illness. and we can make an important, positive difference in the livesof our patients, of all of our patients, but in this context, in patients with hereditaryskin disease. so i think i will stop there and see if thereare any questions or comments. hopefully, i can answer some. like i said, i'm not aparticular expert in this. female speaker:so, diane, there was a question from an attendee who says, "i had a patient with sclerosedfibroma of the nose. the dermatologist recommended p10 testing. is this lesion part of the p10spectrum?" diane seibert:that is a good question, and i don't have

a good answer for that. i would have to -- i'dhave to do a literature search to find that answer myself. i don't know if deborah orerika, 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 aboutthe 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 ofnose, 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 bea cutaneous marker of the disease. i've not come across it myself so i'd have to do alittle more -- i'd have to look it up a bit and see if it actually meets criteria fortesting, 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 thisinformation might be located?

kathleen calzone:so pdq@cancer.gov actually maintains evidence-based reviews of hereditary cancer syndromes andother associated variables. if you go to cancer.gov, you can look at an individual topic, and incowden's, for example, it falls under the genetics of breast and ovarian cancer becauseit's a syndrome that is associated with breast cancer as well as other cancers. and whenyou 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 theclinical criteria associated with the, you know, indications for testing for mutationsin 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 slidewhich 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 anupdate of childhood genetic disorders. so if you have colleagues that are interestedin pediatric conditions, please tell them about how to register for this webinar forapril 26. so i don't see any other questions, so i'mgoing to up the microphones to our presenters just to have one last word before we closeout of the day. deborah, any other parting

comments? deborah macdonald:well, actually i do have a question. diane, that was excellent presentation. thank youso 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 morewe 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 coulddo it pregestationally, with a pgd, pregestational diagnostic testing, or you could test forit prenatally. that's a discussion that, again, these patients should -- in my view, theseconversations should occur prior to conception, certainly. like, what are you going to dowith this information? but the fact is that it does exist, and so hopefully you're notfirst diagnosing something like a cancer syndrome in -- early in pregnancy, and have to thenmake a decision about whether you're going to do prenatal testing. ideally you do thatbefore you ever got pregnant. and it's going to raise a lot of issues over the next decadeor so if the cell-free dna even increases,

potentially increases the sensitivity, decreasingthe 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 sureall 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'scoming 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 ofthese two talks together. i appreciated the -- i really learned a lot from the cancerone, 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 veryrapidly developing era that is changing health

care quite dramatically and will continueto 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, butalso even with others health care providers, including clinicians and others, who may notbe aware of the latest developments. female speaker:well, thank you all -- [end of transcript]