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86 Cards in this Set

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What are some gatekeeper tumor supressor genes? What do gatekeepers do?
Gatekeepers inhibit cell proliferation.

What are some caretaker tumor supressor genes? What to caretakers do?

take care of genomic stability and DNA repair
What are some apoptosis tumor suppressor genes? What do these do?
promote cell death if too much DNA damage accumulates.

p53, HPC1, MSR
lifetime BRCA1 risks?
breast: 50-85%
second breast primary: 50%
ovarian: 15-45%
prostate: 25%
colon (maybe increased?)
what are the differences between BRCA1 and BRCA2
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
what are BRCA2 lifetime cancer risks?
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
what are the disadvantages of the gail model?

*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

*good for women without a significant family history
*provides 5 year risk and lifetime risk to age 90
what are the disadvantages of the claus model?

*includes FDR and SDR (and thus paternal fhx)
*includes age of diagnosis of ca in fhx

*doesnt' include perosnal history factors (menarche, reproductive hx)
*may miss a more distant significant fhx
what does couch model provide? advantages? disadvantages?
provides family risk of having a mtn, then calculates specific person's risk

*separates AJ vs. non-AJ
*breast and ovarian vs. breast alone
*includes FDR and SDR (and thus paternal)

*only BRCA1 risk!
*requires data from at least 4 family members
what dose the BRCAPRO model provide?

advantages? disadvantages?
probability of carrying a BRCA1 or BRCA2 mutation

*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: ??
what is the recommended screening for BRCA carriers?
start at 25yo
clinical breast exam - q6mo
mammogram - annual
MRI - annual

start 25-35yo
transvaginal u/s - annual or semiannual
serum CA 125 - annual or semiannual
what is the recommended screening for lynch?
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)
MEN1 (@11q13) (85% of familial, 65% of sporadic)
*pituitary adenoma (40%)
*parathyroid hyperplasia/adenoma (90%)
*pancreatic - endocrine, islet cell tumors (70%)

other ca: adrenal cortex (36%), thyroid (24%)
which ca syndromes are associated with follicular thyroid ca?
which ca syndromes are associated papillary thyroid ca?
FAP (rare?!)
which ca syndromes are associated with medullary thyroid ca?
MEN2A, B, familial MTC
which ca syndromes are associated with pheo?
pheo, paraganglioma (SDHs)
pancreatic cancer - what syndromes is it seen in?
FAMM - familial atypical mole-malignant melanoma syndrome (90% lifetime risk malignant melanoma, TP16; 17% risk pancreas cancer)
BRCA2 (3-5%)
PJS (33%)
Lynch (2%)
MEN1 (benign adenomas) (70%)
what is the screening protocol for wilm's tumor? what conditions need it?
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
when do you need to rule-out sporadic (non-germline) hypermethylation in lynch tumor testing?
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?)
what are the bethesda criteria for Lynch and what are they used for?
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.
which cancers are considered HNPCC-related cancers in the updated (2004) bethesda guidelines?
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)
what is pathognomonic for Cowden syndrome?
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
which cancer syndromes are ass'd with endometrial cancer
which cancer syndromes are ass'd with ovarian cancer?
which cancer syndromes are ass'd with breast cancer and what is the ass'd lifetime risk?
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
what exposures are people with bloom syndrome sensitive to?
sun, UV, x-ray
inherited oncogene mutations
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
philadelphia chromosome
t(9;22), in CML
precise translocation, leads to fusion gene and protein - BCR-Abl
Burkitt's lymphoma translocations
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
for most cancers, 1-10% of cases are hereditary. which rare tumors are caused by germline mtn >10% of the time?
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
Wilms tumor causes?
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
Aneuploidy cancer risks?
Tri 21 - leukemia
Turner - mosaic or gonadal dysgenesis - increased risk gonadoblastoma - correlates with presence of Y
XXY - breast ca
tri 18 - wilms tumor
RB testing strategy - unliateral vs. bilateral
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
what events are and are not ass'd with LOH in tumors?
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
RB genetic counseling
-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
second cancers in RB?
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
li fraumeni penetrance?
high 90%
women > men, even when sex-specific cancers are eliminated
multiple ca in one patient is very common
li fraumeni cancer risks?
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)
extracolonic features of FAP?
-desmoid tumors - usually in abdomen, painful, hard to treat, recur
-osteomas of jaw, skull, other bones
-epidermoid cysts on face, trunk
-pediatric hepatoblastoma (0.5-1% risk)
-thyroid ca (1% risk)
APC mtn carrier mgmt?
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
Peutz-Jeghers syndrome
LKB1/STK11 on 19p13
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
what is Lynch I?
Lynch II?
Lynch I = CRC only
Lynch II - CRC plus endometrial ca, bild duct, ovarian, ureteral
Cancer risks in classic Lynch?
70% lifetime CRC risk
50-70% lifetime endometrial ca risk
where do Lynch CRCs occur?
bethesda criteria
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
amsterdam criteria
exclude FAP
-at least 1 CRC <50yo
-2 affected generations
-3 affected relatives, 2 are FDR to other one
which two genes make up 80-90% of disease alleles in Lynch?
MSH2 and MLH1
what is unique about MSH6?
mtn may be found even if MSI - low
risk of colon ca is lower (vs. other genes)
what proportion of sporadic CRC are MSI -high?
due to silencing of MLH1 by methylation
Lynch testing algorithm
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
Lynch screening?
colonoscopy every 1-2y starting at 25y
endometrial biopsy

(prophylatic ooph'y being discussed but not part of guidelines)
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
-pancreatic islet cell
-anterior pituitary hyperplasia
-zollinger-ellison synd

MEN1 gene at 11q13, LoF mtns, fxn unknown
-medullary thyroid ca
-parathyroid disease
-missense mtn involving cysteine residues in >90%
-activating mtns
-proph. thyroidectomy by 5yo
presents in infancy
-ganglioneuromas of GI tract, lips, skeletal abnl
-med thyr ca in early childhood (earlier than 2a)
two mtn >95% of cases - M918T>>A883F
activating mtns
proph thyroidectomy by 1yo
BRCA1/2 carrier surveillance guidelines
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
benefits of salpingo-oopherectomy in BRCA carriers?
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
NF1 tumors?
optic gliomas
other CNS tumors
malignant peripheral nerve sheath tumors
NF2 tumors?
8th never/acoustic schwannomas
spinal neurofibromas
TS tumors?
cardiac rhabdoyomas
retinal hamartomas
giant cell astrocytomas
VHL tumors?
-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
when is mosaicism seen in phakomatoeses?
often in the first member of the family dx'd (i.e. de novo)
-can result in negative GT'g
-better to test member of 2nd affected generation, if available
-do tumor or other tissue testing
VHL screening
-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
Gorlin syndrome
-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
genetics of renal cell ca
-histology helps suggest which gene/syndrome
-VHL - almost always clear cell
-birt-hogg-dube - chromophobe/oncocytic histology
-hereditary leiomyomatosis - mtn in fumarate hydratase
-renal cell ca
-benighn fibrofolliculomas
-colon polyps
-medullary thyroid ca
-spontaneous pneumothorax
how is ataxia-telangectasia diagnosed?
elevated AFP or increased radiation sensitivity on clonal assay
how must treatment of patients with ataxia-telangectasia be modified?
reduce dose of ionizing radiation b/c of sensitivity to it
how is fanconi anemia diagnosed?
cells (lymphoblasts and fibroblasts) show increased sensitivity and chromosome breakage after exposure to crosslinking agents:
-diepoxybutane (DEB)
-mitomycin C (MMC)
which biopsy findings are assocaited with increased risk of breast ca?
atypical hyperplasia, RR=2-4
proliferative disease, RR=2-4
rearrangements by ancestry in BRCA1/2
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.
Tamoxifen data in BRCA1/2
-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
OCP use in BRCA1/2 carriers?
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
is genetic testing for li fraumeni recommended in children?
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
what lifestyle modifications are recommended to reduce breast cancer risk in high risk women who don't carry a BRCA1/2 mtn?
-weight control
-discontinue hormone therapy (if approrpriate)
-discontinue smoking
-decreased alcohol consumption

can reduce risk by up to 30-45%

(also - tamoxifen, raloxifene, aromatase inhibitors)
juvenile polyposis
MAD4H(SMAD4) or BMPR1A1 (50%),
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
PJS cancer risks
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
average age of bone marrow failure in fanconi anemia?

i.e. so may present with congenital anomalies or cancer before bone marrow failure develops
predominant mtn type for tumor suppressor syndromes?
missense - VHL

truncating (nonsense, splicing, frameshift) - HBOC, cowden, NF1, FAP
colon cancer risks by order of highest risk for colon cancer syndromes?
FAP - 95%
Lynch - 70%
JPC - 68% (esp. if SMAD4)
PJS - 30%
which RB1 mutations demonstrate low penetrance?
splicing mtn (b/c some normal product made)
what is the DNA repair defect in xeroderma pigmentosum?
can't correct UV-induced DNA lesions correctly. deficient in nucleotide excision repair.
what is usually the first sign of VHL?
retinal hemangiomas (childhood-adolescence), before cancers.
muire torre syndrome
-sebaceous neoplasms of skin - sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, keratoacenthomas
-HNPCC internal malignancies - exhibit MSI

-HNPCC variant
turcot syndrome
-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