DIP Episode 340 - Genetic Syndromes and Cancers for the USMLEs (+ 10/4-8 Step 2CK/3 Course Reminder)

Okay, welcome. My name is Divine. This is episode 340 of the Divine Intervention podcasts. And in this short podcast I'm going to be talking about a high-year topic which I'm going to call Cancer and Genetic Syndrome. The thing is our friends at the MBA means they love to test cancers and their relations to certain and genetic syndromes. So in this podcast I will go over most of the high-year good ones that are classically tested on exams. And then where mechanisms are necessary, our discussed those mechanisms, especially the ones that they would love to test. This is a podcast that will certainly be applicable to anyone taking the USMLE Step 1 to step 3 exams. Now finally I would also say if you're taking the Step 2 CTO Step 3 exams, Sean, I do have a review series of review courses coming up in October. So in the fourth of October I'm going to be having the MBME Testicking Strategies course from 2 to 4 30 PM Pacific Standard Time. And then I'm going to be having the comprehensive Step 2 CTO Step 3 review course between the 5th and the 8th of October. It's going to be from 10 AM to 4 PM Pacific Standard Time over those 4 days. So if you're interested just shoot me an email. I'll give you some more details on the course. The course is classically held over Zoom and I'll give you some more information and once you pay then you can have your spot for the course reserved. So let's just jump right into it. So what if they give you a question about 2-year-old boy?

They tell you that he just came to the pediatrician for a physical exam and the pediatrician notices that this 2-year-old boy has travismas. And then they tell you that his family history is only remarkable. Although he's dead, dead at the age of 35 from malignancy of the boy. If you see this what should you be thinking about? I really hope you're saying ODEVINE. This is a, this chat has a retinoblastoma. So remember retinoblastoma is classically arised from an RB gene mutation. The thing is many of these cancer inheritance syndromes in general they tend to arise in an autosomodominant fashion. That's not always true. But they generally tend to arise in an autosomodominant fashion. So what's the deal with retinoblastoma? Remember retinoblastoma like I said it arises from an RB gene mutation. So many times RB is actually a tumor suppressor gene. It's a gene you find on chromosome 13. It's a tumor suppressor gene. So the thing is that tumor suppressor gene because if you think about it if you have like like some kind of DNA defect then you don't want that cell to keep proliferating. You don't want that cell to go from the G1 phase to the S phase. And usually the way the protein product from the RB gene works is that it binds to something called E2 F. When it binds to E2 F then it prevents right? It prevents you from going from the G1 to the S phase. So the cell does not proliferate and you don't propagate cancer.

You don't propagate mutations that could potentially be be cancerous. But if you have an RB gene mutation that can put you in a really bad spot. Now the thing is this RB gene mutation illustrates something I think I should describe that is called the two-hit hypothesis. The two-hit hypothesis. What do I mean by the two-hit hypothesis? The thing is in general right most genes you have two alleles for those genes. Now the thing is if one allele is mutated already right? Are you going to develop any problem? The answer to that is no. Because usually if one allele for the two-hit hypothesis is mutated that sounds bad. But the thing is the second allele that is normal and is functional is making a new gene product usually to keep cancer and malignancy at B. But when you then go ahead and destroy that second gene then you're getting trouble because now you have no two-hit hypothesis. So you're more predisposed to having malignancy. So in those circumstances those people then go ahead and develop retinoblastoma. So remember again for tumor suppressor genes classically you're going to need two hits right? You need both alleles to be damaged if it's only one right? Because many times when people have like some kind of like heritable retinoblastoma like RB gene mutation typically they would have inherited one of the bad mutations from the appearance but they are fine but then they develop a second mutation and then that's how they subsequently getting trouble. Okay?

Most times it's inherited on nbim exams in an otosomodominant fashion although there's also the types that occur with somatic mutations where the child is not born with any defect so they develop like two somatic mutations and that's how they get in trouble. So that's something that's very high you have to kind of keep in mind for for exams. So again remember many times when people have bilateral retinoblastoma those are usually people that developed the retinoblast RB gene mutation and got it like an a heritable fashion they inherited it from the appearance. Many times when you see people have like unilateral retinoblastoma that's usually more the people that just developed it from like a somatic mutation so that's something to keep in mind. Now remember people that have these RB gene mutations the the ultimately can proceed to get in a not just retinoblastoma but in the future they can proceed to get in osteosarcoma. So remember on nbim exams another name for osteosarcoma is osteogenics or coma right that's why the presence that died of a bone malignancy in the vignette that I give you right. So again this stuff is very very high you to know so don't forget the two-hit hypothesis for too much suppressorations.

Now when they give you a question about a child they tell you that oh he's a 15-year-old boy and his parents bring him to the physician because they notice that for the past two to three weeks he has been having a lot of rectal bleeding right and they tell you that on physical exam you see like dried red blood around the rectum and then they tell you that oh the father you know the father died of colon cancer at the age of 40 right if you see that what you want to think about I really hope you're saying oh divine this person likely has a familial adenomidos polyposis right familial adenomidos polyposis remember many times when people have FAP a classically arises from an APC gene mutation right.

APC again is a tumor suppressor gene it's something you'll find usually if I'm not mistaken on chromosome 5 right on chromosome 5 so the thing is again it's a tumor suppressor gene so you need both genes to be messed up to getting to trouble right to getting to trouble many times again the defect is in herithic in an autosomal dominant fashion right so the thing that happens is again you're probably in herithic one bad gene from your parents and then you develop one mutation in the other gene as a kid was a young adult and then boom the person goes all the way to to colon cancer now it is very high yield to remember that in general these people will have polyps first right I'll say that again these people in general will have polyps first before they proceed to full bloom cancer okay and many times people that have FAP gene I mean APC gene mutations they tend to have that problem arising in the more distal parts of the colon that's not always true but they generally tend to have problems in the more distal distal distal distal parts of the colon that's very high-eautonal right and again those things so they usually their problems will arise distal to the splenic fracture right many times these people have like a ton of rectal polyps right and it's actually kind of high yield to know that these people because they have such a high risk of colon cancer many times around their teenage years you're going to start screening them with colonoscopies many times you do the colonoscopies like every one to two or three years right just to make sure that you're watching those polyps again a lot of the time what physicians usually recommend that what the USML they want you to recommend to those people is that they get like a prophylactic colectomy very early in life when you give them that colectomy they have a very low risk of proceeding all the way to colon cancer and it's very

high you to remember that these APC gene mutations right like you know sometimes people can get I'll say many times people get these problems in an orzo more dominant fashion but if for example you notice that wow the colon cancer seems to be skipping some generations but it then shows up in one generation then I want you to think of something called MUTH or MUTYH or Moody right MUTYH associated that polyposis it's a very similar cancer syndrome to familial adenomatos polyposis but in this case it's actually in herithetin an orzo more recessive fashion so both parents have to be carriers basically the mutation is in something called MUY like COSELIS it's basically something that repairs it's a thing that repairs DNA right so so say for example if you know if guanine gets oxidized because normally we know that guanine usually binds with cytosene right so normally guanine binds with cytosene but if it gets oxidized it can start pairing up with adenine right so the thing that actually fixes that defect is MUY like COSELIS right so if for some reason you have this MUY like COSELIS all messed up again you can begin to develop a very similar phenotype to people that have FAP but you notice that the person like they are immediate parents none of them have colorectal cancer so that tells you that okay both of them are carriers of some mutation the resultimity causing problems in the child so that's very high autonome that's in herithetin an orzo more recessive fashion and again you should also remember that some people that have these APC gene mutations right you can see some of them having like soft tissue tumors right so they can have like like bone tumors they can have these osteomas that's a bone tumor they can have sarcomas when you see those kinds of things what you think of gardener syndrome right I want you to think of gardener syndrome and then if you notice that whi

le these people they have a lot of brain tumors right middle of blastomas glioblastomas then in those circumstances I really want you to think about those people potentially having percote syndrome TUR COT percote syndrome right now one other thing I want to mention with these APC gene mutations is that it is very important to remember that it's not only APC gene mutations that will give you cancer right many times you need to get that APC gene mutation but in addition get all the mutations that's the thing that will take that polyp from going all the way you know that adenomatos polyp from going all the way to colorectal cancer and remember they add anoma to carcinoma sequence right many times they call this AKE53 that's a nice nomonic right so like the APC gene mutation happens first and then after that the KERAS mutation happens and then after that the P53 mutation happens when those things happen in sequence then the person ultimately gets into trouble with colorectal cancer so that's kind of high you to know from an FEP perspective right and then what if they give you a question about a family and the note they tell you that there's family many people seem to have like is almost like a combination of like Gardner syndrome and Turquot syndrome right but you also notice that these people have a lot of leukemias and lymphomas right whenever you see this right you notice a family like you notice that wow they seem to be getting all these brain tumors all these sarcomas getting all these blood tumors these hematologic malignancies like leukemias right and you notice that oh they also have like just other disparate cancers around the body right if you see this I want you to think of something called leaf from an eye syndrome right leaf from an eye syndrome leaf from an eye syndrome this is a really bad cancer syndrome right because one of the biggest highest yield tumo

r suppressor genes is the P53 gene if your P53 gene does not work appropriately that is going to vastly increase your risk of cancer so that we would just need to have the few cancers all over the body now what if they give you a question about a patient and you tell you that this patient multiple family members seem to have developed colorectal cancer right and many of them have no history of polyps on imaging I mean on colonoscopy if you if you ever see something like that I want you to think of something called HMPCC right here D3 look at the name non polyposes so that means the colorectal cancer they get usually does not start with polyps right here D3 non polyposes colorectal cancer HMPCC right so in this syndrome these people the primary problem is usually from like mismatch repair right so the thing is many times the certain parts of DNA called microsatellites they are just like repeat sequences of DNA the thing is many times mismatch repair genes like you know like MLH MSH those things tend to fix any problems that arise in the replication of those micro microsatellites but if you have mutations in MLH MSH and you're not able to take good care of those microsatellites then you can begin to have all these like demisions and stuff that can cause like frame shift mutations in your DNA and obviously if you have a frame shift frame shift mutation that's not a very good thing right that can cause long-term problems so the thing is these people they tend to develop the kinds of cancers that I call CEO cancers that's the nice we remember them on MBM Example so they tend to develop colorectal cancers endometrial cancers and ovarian cancers right again CEO cancers colorectal endometrial and endovarian if you kind of keep these ones in your mind you should be pretty good from that perspective on exams remember many of these people they're going to need a endometrial you'r

e going to do like endometrial biopsies kind of starting around the age 30 roughly in these people and usually try to do it like every like one to two years again just to make sure that they're screened properly for endometrial cancer usually these people they start getting colorectal cancer screening like in their early 20s usually around the age of 20 you're also going to start doing like anewal or you never want to two years colonoscopies in these people to screen them for for colorectal cancer and then what if they give you the question about a family and they tell you that oh in this family maybe let me backtrack a little bit about HMPCC so because I kind of said at the beginning but I want to just make sure it's super super clear because this is something that is super super high you to know for exams it's very important to remember that when people have HMPCC right many times the colorectal cancers they develop do not start with polyps those colorectal cancers do not start with polyps that's one two most times they tend to get very proximal colon cancers like their colon cancers start very very very very very proximal in the colon right so if you see a person having like a sick homoligrancy or an ascending colon maligrancy especially again when they tell you that they have no history of polyps you want to think about linked syndrome and not FAP FAP almost universally those people are going to have polyps and FAP in a great majority of cases they tend to have the polyps in the more distal parts of the colon like the descending colon right the sigmoid colon the rectum right most times people that have FAP problems and most thing they can have cancer colorectal cancers proximal to the splinic fracture but most times the cancers are distal to the splinic fracture it's very very rare to see colorectal cancers slash polyps in in the ascending colon for both have FAPG

mutations right so they almost never develop cancers of the ascending colon but both have linked syndrome they absolutely absolutely positively develop colorectal cancers in the ascending colon so that's very important to know now what if they give you a question about and I think I may actually make this a two-part series but we'll see we'll see let me try to see if I can finish this up here because I have an engagement to run to so what if they give you a question about a family right and they tell you that these people you know they tend to develop the tell you that multiple family members have had like viso cell cancer melanoma scrimal cell cancer of the skin and all those things if you see that right I want you to think of zero-dermar pigment to some xp right so the thing is usually put that have observed dermar pigment to some the problem is in a kind of gaining repair called nucleotide excision repair that's very high you have to know it's usually a problem with nucleotide excision repair nucleotide excision repair so the thing is if you have problems with nucleotide excision repair you're not going to be able to fix a uh uh uh uh uh uh uh uh uh uh uh uh uh pyramidine dimers right so like those time meeting dimers because those things usually develop when people are exposed to ultraviolet light right so uh many times they are managing mutations that can cause ocerotide pigment to some like is anything from xp 8 to xpg so xp 8 xpb xpc anything from xp 8 to xpg right mutations will cause those people to have problems with nucleotide excision repair and those people can unfortunately proceed to develop in a lot of skin cancers right so again when the exposed ultraviolet light that can just cause them significant significant problems and then finally uh just in passing right just want to mention a few key ones these ones they don't really go very deep into mechanisms

behind these on on exams so just give it like the key things you kind of need to know right so don't forget your brachowon and brachar two mutations right these are so they'll pull getting like breast cancers ovarian cancers those are kind of like the big ones right remember these people typically want to screen them with uh anorex mri's between the ages of 25 to 29 was the age of 30 upwards you're gonna give them anorex mri's and mammograms right that's very important to know in these in these patients and remember many times right physicians recommend a prophylactic like you know bilateral mastectomy and also they also get a a t h b s o total abdominal hysterectomy and bilateral sypingo overectomy so you get rid of the breasts the uterus the ovaries the fallopian tubes right and that significantly decreases is almost eliminates these people's risk of developing a of developing malignancy and the thing is brachowon and brachar two mutations their rise from um their rise from people having issues with like homologos recombination it's just a way of fixing a double stand double stranded DNA breaks right and another one that also rises from problems with homologos recombination think of something called bloom syndrome right think of something called bloom syndrome bloom syndrome these people they tend to get a lot of GI tumors but they also tend to get a lot of hematologic malignancies right many times people that have a bloom syndrome uh typically they will have like cafféolee spots right that's very high you they have cafféolee spots and a lot of hematologic malignancies so that's a nice way you can differentiate that from neurofibromatosis type one where they have cafféolee spots but they have a lot of neurofibromas up-techno of giomas right and they can also have like these uh especially if you have like neurofibromatosis type two those people can have like the bil

ateral acoustic neuromus right those problems with cranial nerve 7 and eat so that's kind of high you to know right and then remember fancone syndrome right people that have fancone syndrome again they usually have like thumb abnormalities right many times they can have like a renautubula um sorry um i'm not talking about fancone and in the fancone syndrome whoops i almost we stink myself there but we would have fancone syndrome right just we would tend to get a lot of hematologic malignancies many times they will have like short stature they can have like thumb abnormalities right that's going to be pretty classic in fancone and sometimes we would have fancone that can get like swim cell cancers they can get like liver cancers right so those are all things to to keep in mind and then don't forget one hipole endow right VHL uh those people right again remember it's an ultrasonal dominant problem it's usually on chromosome 3 and those people the big things you want to remember is that you can get hemangioblastomas especially in the posterior fossa right it will be like a a calcified mass in the posterior fossa and they'll usually give you that these people's uh hematochrid is really high because those things make hipo right and they can absolutely cause malignancy and then um remember those people can also get like renal cell carcinomas right especially like bilateral renal cell carcinomas but they can also get pancreatic malignancies and then finally don't forget puegieger syndrome right people that have puegiegers right they have a high risk of pancreatic cancers chlorrectal cancers but remember usually those people they will have like these these are hyper pigmented like macules on their lips right they can get these hyper pigmented macules on their lips right and then obviously we know the ME& syndrome right ME& syndrome especially like ME&1 where these people get

like parathyroid problems pancreatic problems and you know pituitary problems right and then ME&2 A right where they get like you know parathyroid problems but they also get like medallary thyroid cancers and uh fiochromocytomas and then ME&2 B right remember ME&2 B are reching mutations right but ME&1 is a many ME&IN gene mutation they are all all Rosomal dominant inheritance right but would that have ME&2 B they tend to get like medallary thyroid cancers fiochromocytomas they don't have parathyroid problems right remember they tend to have like a Marthenite happiness and um ucosola neuromas so I think those are the big high ill cancer syndrome um I'm gonna go ahead and stop here again I offer tutoring for all the US MLA exams preclinical medical exams 30th shelf exams and then I also um I also uh you know offer again these US MLA step 2 ck step 3 review courses again I'm gonna be making new review courses I'm gonna be bringing them up in the in future podcasts for like people taking other kinds of exams besides step 2 ck step 3 and then um I also help out with ERAS applications personal statements recommendation letters and things of that sort and um again don't forget I have this new website called divine intervention life lessons.com it's a podcast where I post life lessons they're like Bible Bees life lessons all of them are under 10 minutes long and you know many people have said oh divine I love your life lessons so I actually even have it on Apple podcasts as well again divine intervention life lessons.com it's an Apple podcast you can look at for it as the divine intervention life lessons podcast so interestingly many of these things check these things out I have a You Tube channel you can go on the website and even these podcasts I make for this particular website right they are all on Apple podcasts on Google podcasts and on on Spotify so thank you for listening

to me until next time have a wonderful day God bless you thank you

APC gene mutation.

Often involves the proximal colon and can develop cancer without a history of polyps.

Von Hippel-Lindau (VHL) syndrome.

Homologous recombination repair of double-stranded DNA breaks.

Peutz-Jeghers Syndrome.

Familial Adenomatous Polyposis (FAP).

FAP typically involves the distal colon; Lynch Syndrome often affects the proximal colon.

VHL gene mutation (Von Hippel-Lindau syndrome).

Adenoma-Carcinoma Sequence.

Lynch Syndrome (or sometimes Peutz-Jeghers, depending on specific features).

Autosomal recessive (due to oxidative damage/Guanine pairing with Adenine).

Lynch Syndrome.

FAP typically involves the distal colon; Lynch Syndrome often affects the proximal colon.

VHL gene mutation (Von Hippel-Lindau syndrome).

Adenoma-Carcinoma Sequence.

Lynch Syndrome (or sometimes Peutz-Jeghers, depending on specific features).

Autosomal recessive (due to oxidative damage/Guanine pairing with Adenine).

Lynch Syndrome.