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99 Cards in this Set

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  • Back
Pick-up rate of HNPCC with genetic testing
about 60-70%
What is Gardner syndrome?
FAP plus:
desmoid tumors
osteomas
supernumerary teeeth
CHRPE
soft tissue skin tumors
What percent of FAP mutations are de novo?
up to 30%
What type of protein is encoded by MYH?
base excision repair (not tumor supressor)
2 common MYH mutations accounting for 85% of European cases.
Y165C
G382D
MYH mutation common to Indian families
E466X
MYH mutation common to Pakistani families
Y90X
MYH mutation common to Italian families
1395delGGA
What should be done for someone with multiple polyps +/- colon cancer?
take family history
get age of onset
quantify the number of polyps
upper endoscopy to r/o cancers
define size and location of polyps
confirm histology
genetic eval based on results
Asterdam criteria: 3-2-1 rule
THREE relatives affected with HNPCC-associated cancer, one a 1st degree relative of the other 2

TWO generations

ONE cancer before 50
Bethesda criteria
Meet any ONE of these:
Amsterdam criteria met
patient under 50
multiple HNPCC tumors in patient
patient has at least one first degree relative with HNPCC tumor under 50
patient has 2 first or 2nd degree relatvies with HNPCC tumors at any age
patient under 60 and has cancer indicative of MSI
Testing protocol for HNPCC based on meeting criteria
If Amsterdam met, go on with gene testing
If Bethesda met but not Amsterdam, begin with MSI/IHC as screening test
If abnormal, then go on to germline testing
Chemoprevention for Lynch syndrome
NSAIDS
Turcot variant of Lynch is associated with mutations in which genes?
PMS2/MLH1
Very early onset colorectal cancer may be due to what syndrome?
Li-Fraumeni, or homozygous MMR mutations
Which MMR gene is most often seen in homozygous form?
PMS2, MSH6 less often
Features of homozygous MMR mutations
Not typical Lynch-like features
very early onset colorectal cancer
leukemia
brain tumors
cafe-au-lait spots
Features of Peutz-Jeghers
GI hamartomas
lip/mouth pigmentation
colon, stomach, pancreatic, esophageal cancers
cervical adenocarcinoma malignum
ovarian stromal tumors
STK11 gene
lung, small bowel, breast cancers
Gene assoc. with Peutz-Jeghers, and its location
STK11 on chromosome 19
Highest cancer risk in Peutz-Jeghers
colon-40% lifetime risk
Which BRCA gene is assoc. with pancreatic cancer? Which mutation?
BRCA2
AJ mutation 6174delT
How many new breast cancer diagnoses each year? How many deaths?
200,000 cases
40,000 deaths
1700 males cases, 460 deaths
American Cancer Socitey's recommendations for breast cancer screening
Annual mammograms over 40
Annual clinical exams over 40, every 3 years over 20
Self-exams monthly at 20
Breast findings assoc. with no increased risk of cancer
duct ectasia
fibrocystic disease
papillomas, simple fibroadenomas, lipomas
infections
Breast findings assoc. with small increased risk of cancer
ductal hyperplasia without atypia
complex fibroadenomas
sclerosing adenosis
diffuse pappillomatosis
Pathology grades for a tumor
grade 1= well-differentiated
grade 2= moderately differentiated
grade 3= poorly differentiated
Define tumor stages 0-IV
stage 0=in situ
stage I=tumor <2 cm, no nodes
stage II=tumor2-5 cm, +/- nodes
stage III=locally advanced + nodes
stage IV=distant metastases
Treatment for DCIS
excisional lumpectomy + radiation
If estrogen receptor +, give Tamoxifen
With LCIS, how does the risk for invasive caner increase over time?
1% increase per year
Name some drugs used in breast cancer chemotherapy
adriamycin, epirubicin
cytoxan
Methotrexate, 5-flurouracil
taxol, Taxotere
Navelbine
BRCA1 and 2 account for what % of HEREDITARY breast AND ovarian cancer?
about 90%
Name some functions of the normal BRCA1 and BRCA2 genes
DNA repair
cell cycle checkpoint control
ubiquitylation (tagginf proteins for degradation by proteosome)
transcriptional regulation
Lifetime risk of breast cancer for a woman with a BRCA1 mutation? second primary breast cancer?ovarian cancer?
50-85%, often early age of onset
second primary =40-60%
ovarian =30-45%
Other cancers associated with BRCA1
colon, pancreatic, male breast
What kind of factors could greatly underestimate a woman's risk for cancer via the Gail model?
cancer on dad's side
dad's sisters and mom affected (none of the woman's 1st degree relatives)
ovarian cancer
very early onset
Protective factors for breast cancer
4+ hours per week of exercise
breastfeeding
ideal bpdy weight, esp. after menopause
having kids before 30
Claus tables take only what single factor into account when estimating risk?
family history
Name 4 syndromes associated with hereditary breast cancer
HBOC, Li-Fraumeni, Cowden, Peutz-Jeghers
BRCA1 and 2 account for what % of HEREDITARY breast cancer?
about 50%
In an MSI study, what are the uidelines for determining whether the tumor is MSI-high or not?
more than 30% unstable=MSI high
less than 30% = MSI low
0% unstable =MSI-stable
Another name for microsatellites
SSRs-simple sequence repeats
The repeated sequence in microsatelites are how long?
1-6 base pairs
In MSI testing, what do you do if the tumor is found to be MSI-high?
Do IHC testing to determine which gene to sequence OR sequence MLH1 and MSH2
In MSI testing, what do you do if the tumor is found to be MSI-low or stable?
Consider colon cancer surveillance, consider IHC testing
IHC is most useful for which genes, and why?
MSH2 and MSH6, because most patients with MSH2 mutations have germline mutations. Sporadic patients often have MLH1-negative tumors.
Limits of IHC testing
1. If tumor is MSI-high and no mutations are found by IHC, may need to seq. all genes
2. Can't detect missense mutations if protein still localizes.
What would you do for a tumor in which MSI is high and IHC is abnormal, but sequencing yields no results?
Up to 20% have large deletions or rearrangements. Do MLPA or Southern.
What is the possible order of complete testing that may be necessary to find a mutation causing HNPCC?
1. MSI and IHC
2. methylation studies if MLH1 if abnormal
3. Gene scanning followed by sequencing
4. MLPA or Southern to look for deletions
Name some problems with protein truncation testing
A large deletion won't show a band, and only the normal allele will be seen, so will look normal. Same is true for RNA processing mutations, or anything that doesn't lead to a truncated protein. Would result in a false negative.
What are some examples of when to use linkage analysis?
1. When no mutation is identified in any affected family member
2. If the affected family member isn't available, but others are
3. non-disclosing prenatal diagnosis for adult-onset conditions (rule out inheritance of affected grandparent's chromosome)
Linkage is still used to diagnose what condition?
DMD/BMD
Cancer risk factors in an indivdual that indicate the need for referral to genetics
1. bilateral primary tumors
2. multifocal tumors
3. atypical age/sex/site
4. rare tumor
5. tumor assoc. with birth defect, genetic disease, precursor lesion
What indicates a genetics referral for cancer in one's family?
1. a first-degree relative with a cancer, who has any of the individual risk factors
2. Two first-degree relatives with any cancer
Penetrance of MEN1 and MEN2
Almost 100% by age 50
Diagnostic criteria for NF1
2 of these manifestations:
--6 cafe-au-lait spots over 15mm postpubertal
--1 plexiform neurofibroma or 2 other neurofibromas
--axillary or inguinal freckling
--2 Lisch nodules
--optic pathway tumor
--characteristic osseous dysplasia
--affected first-degree relative
Diagnostic criteria for NF2
Bilateral vestibular schwannomas
OR
a first degree relativve with NF2 and you have
1. unilateral vestibular schwannoma under 30 years
OR
2. Two of the following: mengioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract
Name some categories of protooncogenes
1. tyrosine kinases (ERBB2/HER2, RET, ABL)
2. Guanine nucleotide exchangers and bindig proteins (NF1, BCR)
3. Nucelar proteins and Tx factors (GLI, MYC, WT1)
4. Cell cycle/DNA damage response (ATM, MLH1, MSH2, TP53)
Name some tumor suppressor genes
APC, NF1, NF2, BRCAs, VHL, RB1
Explain the difference in inheritance of protooncogenes vs. tumor suppressors
Protooncogenes are dominant in that they take only 1 hit to cause cancer. Not inherited. Tumor suppressors require 2 mutations, so are recessive on some level. May be inherited or not inherited.
What is the cancer risk associated with mosaic trisomy 8?
preleukemia
Name some chromosome abnormalities assoc. with increased cancer risk?
mosaic tri 8
tri 21
del 11q13 (WT)
del 13q14 (RB)
Turner
Klinefelter
What is the cancer risk associated with Turner syndrome?
endometrial adenosquamous carcinoma
What is the cancer risk associated with Klinefelter?
nongonadal germ cell tumor and breast cancer
What is Boveri's 1914 hypothesis about cancer?
All malignancies have abnormal chromosomes (or genes)
Name 4 cytogenetic rearrangements that can be associated with familial cancer
12;13 (familial retinoblastoma)
8;N (familial renal cell carcinoma)
11;N (familial Wilms tumor)
14;22 (familial meningioma)
Explain the Philadel[phia chromosome
Translocation 9;22 in chronic myelogenous leukemia (CML), results in variable fusion between Abelson protooncogene, abl, and BCR gene (a protein kinase)
Explain cancer translocation btwn 15;17
In acute progranulocytic leukemia, results in fusion protein of zinc protein type (PNL) with retinoic acid receptor alpha (RARA); make leukemia sensitive to retinoic acid therapy--may be curative
Name that cancer type:
t(X;8)
t(12;16)
t(X;8)=synovial cell sarcoma
t(12;16)=liposarcoma
Name 3 cancer types associated with t(11;22)
Ewing sarcoma
skin tumor
peripheral neuroepithelioma
Genes associated with Lynch syndrome
MLH1/3
MSH2/6
PMS1/2
Syndrome associated with papillary renal cell carcinoma
MET (protooncogene)
2 main genes associated with Li Fraumeni syndrome
TP53, CHK2
Guidelines to meet for Li Fraumeni
1. Any sarcoma under 45 years
2. 1st degree relative with any cancer under 45 years
3. 1st or 2nd degree relative with any cancer under 45 oR sarcoma at any age
Describe the common findings of phakomatoses
1. congenital and hereditary developmental anomalies
2. tumor-like malformations with blastomatous tendencies
3. pigmentary patches and/or angiomas
4. tissues of ectodermal origins (skin, eye, nervous)
5. some mesodermal and endodermal elements
type of phakomatosis in Sturge-Weber
encephalotrigeminal angiomatosis
Frequency of NF1 vs. NF2
NF1=1 in 4000
NF2=1 in 40,000
Gene and location of NF1 vs. NF2
NF1= neurofibromin (17q)
NF2= merlin (22q)
Tumor types in NF1 vs. NF2
NF1=neurofibroma, glioma, sarcoma, pheochroma
NF2=vestibular schwannoma, mengioma
Skin findings in NF1 vs. NF2
NF1=cafe-au-lait spots, skin-fold freckling, dark spots
NF2=rare spots, neurofibromas
Cognitive impairment in NF1 vs. NF2
NF1=hand-eye coordination impaired
NF2=normal
Calcifications on brain MRI
Teeth pits
What syndrome?
Tuberous sclerosis
Name the primary diagnostic features of tuberous sclerosis
cortical tubers
subependymal hamartomas
retinal hamartomas
angiofibroma (skin)
ungual fibroma (nails)
What feature of tuberous sclerosis might show up on prenatal ultrasound?
rhabdomyoma in heart
What are subependymal hamartomas in tuberous sclerosis?
Growths on lining of the brain ventricles
Name the 2 genes and locations assoc. with tuberous sclerosis
TSC1=hamartin, 9q34
TSC2=tuberin, 16p13
In von Hippel-Lindau, angiomas can appear in which 3 areas?
liver
adrenal gland
retina
Major features of von Hippel-Lindau
retinal ,liver, and adrenal angiomas
cerebellar and spinal cord hemangioblastomas
other tumore: pheochromocytoma, carcinoma of kidney, pancreas, endolymphatic sac (in cochlea of ear)
cysts of kidney, pancreas (acinar and islet cell), epididymis
Gene and location of von Hippel-Lindau
VHL, chromosome 3, elongin binding protein
What is Klippel-Trenaunay-Weber syndrome?
Skin hemangioma of limb, extends to trunk. Hypertrophy of involved limb. Varicose vein. At risk for high-output heart failure. Congenital but NOT hereditary.
Describe Proteus syndrome
hemihypertrophy, gigantism of digits, lipoma, angioma, nevus, conjunctival dermoid, skull hyperstosis, renal and lulng cysts, hyperpigmentation spots, plantar hyperkeratosis
Features of Gorlin syndrome (nevoid basal cell carcinoma syndrome)
multiple basal cell carcinomas
pits of palms and soles
cysts of jaw bone and phalanges'
rib anomalies (fused, bifid)
medulloblastoma
ovarian fibroma and cancer, even very young
may see eyelid tumors, axillary tags, synophrys
Gene and location of Gorlin syndrome.
Patched on 9q
Due to haploinsufficiency
Features of Cowden syndrome
Warty papules at mucocutaneous junctions
papillomas in mouth and tongue
palmar hyperkeratoses
thyroid neoplasia
breast cancer
colon cancer and polyps
meningioma
Name some syndromes assoc. with PTEN gene
Cowden
Lhermitte-Duclos
juvenile intestinal polyposis
Bannayan-Riley-Ruvalcaba
Ruvalcaba-Myhre-Smith
Somatic: endometrial and prostate carcinoma, melanoma
What syndrome?
macrocephaly
freckles, esp. in mouth and around eyes
cutaneous myxomas
Sertoli cell tumors
Carney complex (LAMB or NAME)
Features of Carney complex
Myxoma of skin
myxoid breast fibroadenoma
lentigenes or blue nevi
pigmented nodular adrenal disease
Sertoli cell tumor, pituitary adenoma
Schwannoma
What is Carney triad (no relation to Carney complex)?
Gastric tumor (leiomyosarcoma)
pulmonary chondroma
extra-adrenal paraganglioma

mostly affects young women, low familiality
Another name for ataxia telangiectasia
Louis-Bar syndrome
Heterozygotes for ataxia telangiectasia (carriers) may have increased risk of what?
breast cancer