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86 Cards in this Set
- Front
- Back
What are some gatekeeper tumor supressor genes? What do gatekeepers do?
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Gatekeepers inhibit cell proliferation.
APC, NF1, VHL, PTEN |
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What are some caretaker tumor supressor genes? What to caretakers do?
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MSH2, ATM, BRCA1
take care of genomic stability and DNA repair |
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What are some apoptosis tumor suppressor genes? What do these do?
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promote cell death if too much DNA damage accumulates.
p53, HPC1, MSR |
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lifetime BRCA1 risks?
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breast: 50-85%
second breast primary: 50% ovarian: 15-45% prostate: 25% colon (maybe increased?) |
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what are the differences between BRCA1 and BRCA2
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cancer risks - BRCA1 has a higher risk of ovarian cancer and is more frequently seen in families with ovarian ca.
prevalence - BRCA1 accounts for more HBOC famlies than BRCA2 path - BRCA1 mutations are usually triple negative (ER, PR, her2neu) BRCA2 is associated with more 'other' cancers - male breast, pancreas, other rare |
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what are BRCA2 lifetime cancer risks?
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breast: 50-85%
ovarian: 10-27% male breast: 6-14% prostate: 20% (?beth crawford - 4.7%) pancreas (3.5%), melanoma (2.6%), stomach (2.5%), biliary tree (5%), other rare - increased |
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what are the disadvantages of the gail model?
advantages? |
disadvantages:
*doesn't include SDR (and thus paternal fhx) *doesn't include age of diagnosis in fhx *doesn't include history of other cancers, such as ovarian advantages: *good for women without a significant family history *provides 5 year risk and lifetime risk to age 90 |
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what are the disadvantages of the claus model?
advantages? |
advantages:
*includes FDR and SDR (and thus paternal fhx) *includes age of diagnosis of ca in fhx disadvantages: *doesnt' include perosnal history factors (menarche, reproductive hx) *may miss a more distant significant fhx |
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what does couch model provide? advantages? disadvantages?
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provides family risk of having a mtn, then calculates specific person's risk
advantages: *separates AJ vs. non-AJ *breast and ovarian vs. breast alone *includes FDR and SDR (and thus paternal) disdvantages: *only BRCA1 risk! *requires data from at least 4 family members |
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what dose the BRCAPRO model provide?
advantages? disadvantages? |
probability of carrying a BRCA1 or BRCA2 mutation
advantages: *FDR and SDR fhx *includes unaffected relatives *includes history of breast and ovarian *bayesian calculation that includes age, degree of r'ship, penetrance, incidence, etc. disadvantages: ?? |
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what is the recommended screening for BRCA carriers?
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breast:
start at 25yo clinical breast exam - q6mo mammogram - annual MRI - annual ovary: start 25-35yo transvaginal u/s - annual or semiannual serum CA 125 - annual or semiannual |
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what is the recommended screening for lynch?
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colonoscopy every 1-2y, starting at 25yo
(v. effective - halves the risk, decreases mortality by 65%) note that in lynch it takes less time (2-3y) for a polyp -> tumor than the general population (8-10y) |
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men1
MEN1 (@11q13) (85% of familial, 65% of sporadic) |
3Ps:
*pituitary adenoma (40%) *parathyroid hyperplasia/adenoma (90%) *pancreatic - endocrine, islet cell tumors (70%) other ca: adrenal cortex (36%), thyroid (24%) |
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which ca syndromes are associated with follicular thyroid ca?
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cowden
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which ca syndromes are associated papillary thyroid ca?
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FAP (rare?!)
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which ca syndromes are associated with medullary thyroid ca?
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MEN2A, B, familial MTC
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which ca syndromes are associated with pheo?
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VHL
pheo, paraganglioma (SDHs) NF1 MEN2A MEN2B |
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pancreatic cancer - what syndromes is it seen in?
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FAMM - familial atypical mole-malignant melanoma syndrome (90% lifetime risk malignant melanoma, TP16; 17% risk pancreas cancer)
BRCA2 (3-5%) PJS (33%) ATM Lynch (2%) FAP LFS MEN1 (benign adenomas) (70%) |
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what is the screening protocol for wilm's tumor? what conditions need it?
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Abdominal Ultrasound every 4 months until age 7-8 years
In BWS, serum AFP every 3-4 months until age 3 years (for risk of hepatoblastoma) BWS, WAGR, Denys-Drash, AD isolated WIlm's, isolated hemihypertrophy, frasier syndrome |
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when do you need to rule-out sporadic (non-germline) hypermethylation in lynch tumor testing?
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if IHC shows loss of MLH1 or PMS2, could be sporadic hypermethylation. need to run hypermethylation studies on the tumor. also test for BRAF V600E b/c it is mutually exclusive with MLH1 germline (and the cause of sporadic hyermeth?)
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what are the bethesda criteria for Lynch and what are they used for?
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used to decide who to do tumor testing on, NOT diagnostic criteria.
updated (2004) bethesda criteria: *Colorectal cancer diagnosed in an individual younger than than age 50 years * Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors 1, regardless of age * Colorectal cancer with the MSI-H histology (not MSI-H, just suggestive histology) 2 diagnosed in an individual younger than age 60 years *Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one cancer diagnosed before age 50 years *Colorectal cancer diagnosed in two or more first- or second-degree relatives of any age. |
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which cancers are considered HNPCC-related cancers in the updated (2004) bethesda guidelines?
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crc, endometrial, stomach, ovarian, *pancreas, ureter and renal pelvis, billiary tract and *brain (usually glioblastoma)
(vs. amsterdam II criteria, HNPCC-ass'd ca is Colorectal, endometrial, stomach, *small intestinal, hepatobiliary, renal pelvic, or ureteral) |
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what is pathognomonic for Cowden syndrome?
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adult (not childhood) lhermitte-Duclos disease (LDD) - defined as presence of cerebellar dysplastic gangliocytoma - a hamartomatous overgrowth
mucocutaneous lesions (99% penetrant by 3rd decade): *trichilemmomas (facial, may mimic wart of basal cell ca) *acral keratoses (flesh-colored or slightly pigmented smooth or warty papules on upper surface of hands and feet) *papilomatous lesions |
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which cancer syndromes are ass'd with endometrial cancer
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Lynch
Cowden |
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which cancer syndromes are ass'd with ovarian cancer?
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BRCA1/2 / HBOC
Lynch |
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which cancer syndromes are ass'd with breast cancer and what is the ass'd lifetime risk?
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BRCA1/2 - 28-87%
p53/LFS - 90% overall ca risk, 60% breast ca risk Cowden/PTEN - 25-50% PJS - 32% diffuse gastric ca/CDH1 - lobular ca risk - 39% ATM hets - RR =2.0 CHEK2, PALB2 RR=2.0 |
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what exposures are people with bloom syndrome sensitive to?
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sun, UV, x-ray
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inherited oncogene mutations
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RET - MEN2a,b
MET - hereditary papillary renal cell ca HRAS - Costello syn (incl'g bladder ca, neuroblastoma, rhabdomyosarcoma) KRAS - CFC (no cancer pheno) ALK - hereditary neuroblastoma |
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philadelphia chromosome
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t(9;22), in CML
precise translocation, leads to fusion gene and protein - BCR-Abl |
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Burkitt's lymphoma translocations
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imprecise - place c-myc (from 8) near consitutive promoter, at site of immunoglobin loci
t(8;14 or 2 or 22) no fusion protein made |
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for most cancers, 1-10% of cases are hereditary. which rare tumors are caused by germline mtn >10% of the time?
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RB - 40% RB1
adrenocortical carcinoma - 50% p53 pheo/paragang - 25% heredtiary - VHL, NF1, RET, SDHB,D retinal or cerebellar hemangioblastoma - VHL optic pathway tumor, malignant peripheral nerve sheath tumor, JMML - NF1 optic glioma - 45% NF1 juvenile myelomoncytic leukemia - 40% NF1 medullary thyroid ca - RET acoustic or vestibular schwannomas - NF2 |
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Wilms tumor causes?
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WAGR - 11p15 cytogenetically visible del including WT1
Dennys-Drash - 11p15 WT1 point mtn AD Willm's - single gene disorder, locus unknown (not 11p15) BWS - 11p13 - loss or gain of imprinting, del, UPD, mtn trisomy 18 |
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Aneuploidy cancer risks?
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Tri 21 - leukemia
Turner - mosaic or gonadal dysgenesis - increased risk gonadoblastoma - correlates with presence of Y XXY - breast ca tri 18 - wilms tumor |
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RB testing strategy - unliateral vs. bilateral
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bilateral - analyze RB1 directly from blood
unilateral - analyze RB1 in tumor AND blood - identify both 'hits' in tumor and see if one is found in blood |
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what events are and are not ass'd with LOH in tumors?
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ass'd with LOH:
-loss of whole chromosome -loss of chromosme and reduplicaiton fo chromosome w mtn -loss of whole arm or large interstitial del -mitotic recombination between chromosomes not ass'd with LOH: -point mtn or intragenic del'n -silencing of gene by meth'n of promoter |
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RB genetic counseling
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bilateral
-all bilateral cases considered constitutional/germline w 80% de novo -parents should have dilated eye exam and genetic testing -if parents evals normal - 7% sibling recurrence risk b/c of germline mosaicism unilateral cases -13-15% are constitutional -no clear predictor of which cases -if parents evals normal - 1% sibling recurrence risk |
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second cancers in RB?
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70% risk by age 50 for second primary
-bone and soft tissue sarcomas most common childhood ca -adulthood - epithelial tumors (eg. lung) -radiation therapy increases risk, esp. for sarcomas |
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li fraumeni penetrance?
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high 90%
women > men, even when sex-specific cancers are eliminated multiple ca in one patient is very common |
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li fraumeni cancer risks?
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overall - 90%
breast - 60% soft tissue sarcoma - 29% brain - 28% osteosarcoma - 14% leukemia - 14% adrenocorticol - 5% (but 60% of all adrenocorticol pt have p53 mtn) |
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extracolonic features of FAP?
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-desmoid tumors - usually in abdomen, painful, hard to treat, recur
-osteomas of jaw, skull, other bones -epidermoid cysts on face, trunk -CHRPE -pediatric hepatoblastoma (0.5-1% risk) -thyroid ca (1% risk) |
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APC mtn carrier mgmt?
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colonoscopy beginning 10-12yo, every 1-2y
colectormy by late teens to early 20s (poly load or dysplasia) upper GI endoscopy for risk of gastric adenomas and duodenal ca annual thyroid exam |
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Peutz-Jeghers syndrome
LKB1/STK11 on 19p13 |
AD
point mtn (45%), del (50%)-- more dels than other tumor supressor syndromes -pigmented spots on lips, buccal mucosa, GI tract -hamartomas of small and large bowel -intussusception - serious complications -cancer risk in adults: --lifetime ca risk 81% --GI (small int, CRC, esophageal, pancreatic) - 66% --breast - 32% in women (MRI surveillance) -benign ovarian sex-cord tumors w annular tubules -sertoli-cell testicular tumors |
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what is Lynch I?
Lynch II? |
Lynch I = CRC only
Lynch II - CRC plus endometrial ca, bild duct, ovarian, ureteral |
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Cancer risks in classic Lynch?
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70% lifetime CRC risk
50-70% lifetime endometrial ca risk |
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where do Lynch CRCs occur?
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right-side
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bethesda criteria
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based on proband characterisitcs
-CRC <50yo -CRC + HNPCC assoc ca -FDR w 2 HNPCC ca, on <50yo -2 SDR, one with CRC and one with HNPCC ass'd ca |
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amsterdam criteria
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exclude FAP
-at least 1 CRC <50yo -2 affected generations -3 affected relatives, 2 are FDR to other one |
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which two genes make up 80-90% of disease alleles in Lynch?
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MSH2 and MLH1
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what is unique about MSH6?
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mtn may be found even if MSI - low
risk of colon ca is lower (vs. other genes) |
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what proportion of sporadic CRC are MSI -high?
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~20%
due to silencing of MLH1 by methylation |
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Lynch testing algorithm
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most programs:
-IHC or MSI on tumor of affected family member -if MSI+ or IHC shows missing protein (and not due to somatic meth'n of MLH1), then do mtn analysis of MSH2, MLH1, MSH6 -need copy number analysis of MSH2 b/c deletions are common |
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Lynch screening?
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colonoscopy every 1-2y starting at 25y
endometrial biopsy (prophylatic ooph'y being discussed but not part of guidelines) |
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Turcot
-inheritance? -genes? -pheno? |
AR
MMR genes - biallelic inactivation -brain tumors -colon polyps/cancer in childhood -brain tumors and t-cell leukemias and lymphomas are more common than colon cancers -atypical cafe au lait spots and axillary freckling |
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MEN1
-tumors? |
tumors
-parathyroid -pancreatic islet cell -anterior pituitary hyperplasia -zollinger-ellison synd MEN1 gene at 11q13, LoF mtns, fxn unknown |
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MEN2A
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-medullary thyroid ca
-pheo -parathyroid disease -missense mtn involving cysteine residues in >90% -activating mtns -proph. thyroidectomy by 5yo |
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MEN2B
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presents in infancy
-ganglioneuromas of GI tract, lips, skeletal abnl -pheo -med thyr ca in early childhood (earlier than 2a) two mtn >95% of cases - M918T>>A883F activating mtns proph thyroidectomy by 1yo |
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BRCA1/2 carrier surveillance guidelines
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BSE - monthly
CBE - q6-12mo, start at 25yo mammo - q6-12mo, start at 25yo MRI - annual, stat at 25yo serum CA125 - q12 mo, start 25-35yo (no evidence efficacy) transvag. u/s q12mo, start 25-35yo |
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benefits of salpingo-oopherectomy in BRCA carriers?
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90% reduction in ovarian cancer risk
~50% reduction in breast ca risk (esp. if done mid 30s to early 40s) recommended at 35-40yo, after childbearing |
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NF1 tumors?
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optic gliomas
other CNS tumors malignant peripheral nerve sheath tumors pheos |
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NF2 tumors?
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meningiomas
8th never/acoustic schwannomas spinal neurofibromas |
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TS tumors?
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cardiac rhabdoyomas
retinal hamartomas giant cell astrocytomas |
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VHL tumors?
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-retinal angiomas - one of earliest signs
-retinal, cerebellar, spinal hemangioblastomas -start in adolescence, leading cause of early mortality -renal cell ca - young adult -pheos (highly dependent on specific mtn type and location, occur in childhood through adulthood) -others (more rare) - pancreatic, endolympatic sac |
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when is mosaicism seen in phakomatoeses?
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often in the first member of the family dx'd (i.e. de novo)
NF2~TSC>VHL>NF1 -can result in negative GT'g -better to test member of 2nd affected generation, if available -do tumor or other tissue testing |
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VHL screening
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-ophtho - annual, from infancy
-endocrine - urinary catecholamines or plasma metanephrines - from 2yo, every 1-2y -MRI of brain and spine - from 11yo, every 2y -abd'l CT or u/s - from 11yo u/s yearly, from 20yo CT yearly |
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Gorlin syndrome
PTCH |
-multiple nevoid basal cell ca in teens
-esp. in field of radiation therapy -odontogenic jaw cysts, bifid ribs, prominent forehead, calcification of falx cerebri, plantar and palmar pits -medulloblastoma (4-5% risk) - annual MRI |
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genetics of renal cell ca
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-histology helps suggest which gene/syndrome
-VHL - almost always clear cell -birt-hogg-dube - chromophobe/oncocytic histology -hereditary leiomyomatosis - mtn in fumarate hydratase |
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birt-hogg-dube
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-renal cell ca
-benighn fibrofolliculomas -colon polyps -medullary thyroid ca -spontaneous pneumothorax - |
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how is ataxia-telangectasia diagnosed?
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elevated AFP or increased radiation sensitivity on clonal assay
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how must treatment of patients with ataxia-telangectasia be modified?
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reduce dose of ionizing radiation b/c of sensitivity to it
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how is fanconi anemia diagnosed?
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cells (lymphoblasts and fibroblasts) show increased sensitivity and chromosome breakage after exposure to crosslinking agents:
-diepoxybutane (DEB) -mitomycin C (MMC) |
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which biopsy findings are assocaited with increased risk of breast ca?
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atypical hyperplasia, RR=2-4
proliferative disease, RR=2-4 |
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rearrangements by ancestry in BRCA1/2
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no large rearrangements seen in AJ, Asians, middle easterns
16% of positive tests in AA are rearrangements (but that's because so many point mtn get called as VUS??) 10% of positive test results in Europeans are rearrangements. |
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Tamoxifen data in BRCA1/2
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-reduces risk by 45% in "high risk" women (not mtn carriers)
-case-control study - reduced risk of contralateral breast ca in mtn carriers -RCT - may not be effective in BRCA1, but is effective in BRCA2 |
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OCP use in BRCA1/2 carriers?
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may reduce ovarian cancer risk - 60% reduction, especially if taken in 20s and 30s
but in women with fhx breast cancer, OCP may increase breast ca risk more than for other women |
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is genetic testing for li fraumeni recommended in children?
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not generally. it's controversial.
b/c lack of effective interventions or screening, possible adverse psych out comes, inability of minors to provide adequate informed consent |
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what lifestyle modifications are recommended to reduce breast cancer risk in high risk women who don't carry a BRCA1/2 mtn?
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-weight control
-exercise -discontinue hormone therapy (if approrpriate) -discontinue smoking -decreased alcohol consumption can reduce risk by up to 30-45% (also - tamoxifen, raloxifene, aromatase inhibitors) |
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juvenile polyposis
MAD4H(SMAD4) or BMPR1A1 (50%), PTEN |
AD
colonic, small intestine onset: 5-10yo fhx positive in 20-50% of cases intussesception and bleeding are frequent symptoms juvenile polyp = hamartoma, specific histology -there is a JPS/HHT overlap syndrome |
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PJS cancer risks
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all cancer - 81%
GI - 66% -CRC - 30% -pancreatic - 8% breast - 32% gyn - 13% lung - 7% rare cancers seen in PJS: adenoma malignum of cervix, sex cord tumor, sertoli cell tumor |
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average age of bone marrow failure in fanconi anemia?
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6yo
i.e. so may present with congenital anomalies or cancer before bone marrow failure develops |
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predominant mtn type for tumor suppressor syndromes?
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missense - VHL
truncating (nonsense, splicing, frameshift) - HBOC, cowden, NF1, FAP |
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colon cancer risks by order of highest risk for colon cancer syndromes?
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FAP - 95%
Lynch - 70% JPC - 68% (esp. if SMAD4) PJS - 30% |
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which RB1 mutations demonstrate low penetrance?
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splicing mtn (b/c some normal product made)
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what is the DNA repair defect in xeroderma pigmentosum?
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can't correct UV-induced DNA lesions correctly. deficient in nucleotide excision repair.
|
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what is usually the first sign of VHL?
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retinal hemangiomas (childhood-adolescence), before cancers.
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muire torre syndrome
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-sebaceous neoplasms of skin - sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, keratoacenthomas
-HNPCC internal malignancies - exhibit MSI -HNPCC variant |
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turcot syndrome
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-HNPCC variant
-CRC or CR aenomas -turmos of CNS - +/- polyposis -APC mtn or mismatch repair mtuation - APC mtn - more polyps, more likely to have medulloblastoma as the CNS tumor - MMR mtn - fewer polyps, more likely to have glioblastoma as the CNS tumor, MSI in brain tumors |