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102 Cards in this Set
- Front
- Back
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Risks Associated with Breast Biopsy Findings
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Slight increase risk (proliferative w/out Atypia) :hyperplasia, moderate or florid, sclerosing adenosis
Moder increase (Atypia): atypical ductal hyperplasia High Risk: DCIS and LCIS |
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Atypical Hyperplasia
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-20-25% lifetime without family history of breast
-up to 40% with family history of breast |
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DCIS Risk of invasive cancer
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30%
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LCIS Risk of Invasive Cancer
Features of LCIS |
-25-30%
-multicentric and frequently bilateral |
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Gail Model Cons
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-Does not factor in second degree relatives, paternal history, age at diagnosis in relatives
-can underestimate risk |
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Function of BRCA1 and BRCA2 genes
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-Homologous recombination DNA repair
-Cell cycle checkpoint control -Ubiquitylation -transcriptional regulation |
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How do PARP inhibitors work?
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-enzyme in DNA base exision repair
-cells with BRCA1/2 mutations are deficient in homologous recombination DNA repair but STILL have base excision repair -By blocking PARP cell has no excision repair and it dies -Spares normal cells |
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BRCA1 : function, gene location, Inheritance, cancer risks
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Tumor suppressor gene ch 17, AD, protein has role in genomic stability, rearrange in approx 10 percent
- breast cancer risk : 50-85 % - second primary 40-60% - ovarian 30-45% |
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BRCA2 : function, gene location, Inheritance, cancer risks
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- tumor suppressor
- role in genomic stability -AD - 10% large deletion s -breast cancer: 50-85% - male breast: 5-10% - ovarian: 10-20% - prostate 5-10% - pancreatic: 5-10% - melanoma: 3-5% -BRCA2 mutations have been reported in specific familial pancreatic families - seen in about 6% of mod to high risk pancreatic cancer families - BRCA2 is also FANCD1 |
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bRCA2 and Fanconi Anemia
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Fa rare AR disease of childhood
Increased risk of leukemia Increased risk of hematologic and solid brain cancers Bialleleic mutations in PALB2 BRIP1 and RAD51C also lead to FA |
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Founder mutations AJ
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185delAG ( 1%), 5382insC (0.15%), 6174delT (1.5%)
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Chemo prevention
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Tamoxife, raloxifen
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Li- Fraumeni sx
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Tp53, ch17
50% risk by age 35 90% for women 70% for men Breast (most frequent) Other: sarcoma, brain leukemi, childhood adrenal cortical rumors, - four core cancers: sarcoma, brain, tumor breast cancer ACC Choroid plexus tumor* * adrencocortical carcinoma strongly predictive -7-20% de novo |
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Cowden sx
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AD
Macrocephaly Trichilemmomas/ papillomas by 20's Breast (25-50%) follicular thyroid (10%)and uterine (50%) Additional features : hamartomatous intestinal polyps, lipomas, fibromas, uterine fibroids, fibrocystic dx, autism spectrum |
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Lhermite- duclose dx
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Variant of cowden
Cerebellar dy plastic gangliocytomas, rare benign tumor in 30's and 40's with hydrocephalus |
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What are other PTEN dx?
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Bannayan - Riley-Ravacalba
Proteus sx |
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Bannayan Riley Ruvacalba
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multiple subcutaneous lipomas, macrocephaly and hemangiomas lipomas
AD |
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Proteus syndrome
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hh
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risk factors for CRC
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Personal history of neoplasm, inflammatory bowèl disease
Hnpcc mutation |
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Causes of Hereditary susceptibility
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Sporadic 65-85%
Familial 10-30% HNPCC 5% FAP 1% |
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FAP
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AD
APC tumor suppressor 30% de novo >100 adenomas Risk of extra colonic rumors: upper GI, Desmond, osteoma, thyroid, brain, hepatoblasma) 100% risk of cancer |
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Gardeners syndrome
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Desmoid rumors, osteomas, supernumerary teeth, CHRPE, soft skin tumor a
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Attenuated FAP
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Late onset CRC age 50
few colonic adenomàs usually > 20but < 100 polyps Not associated with CHRPE Upper GI lesions Associated with mutations 5' and 3' ends of APC gene |
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Clinical management FAP
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Annual colonoscopy until until polyposis
Colectomy Annual upper endoscopy Chemo prevention Monitoring |
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MYH(MAP)
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Recessive colon polyposis
MYH is involved in base excision repair At least 15 polyps , fewer than 100 Polyps are adenocarcinoma may be hyper plastic Common mutations: Y165C and G382D Carrier 1% of MYH |
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MYH
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Increase in risk for duondenal cancer
- 17% chance of deondenal cancer - 4% lifetime for duondenal Higher incidence of ovarian, bladder, skin cancer |
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Hereditary colon cancer
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hh
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Amsterdam Criteria
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3 or more relatives with verified CRc in family
One case a 1st degree relative - of the two Two or more generations One CRC by age 50 FAP |
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Revised Bethesda guidelines
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CRC did <50 yrs
CRC that are synchronous or metaphor us or other tumor a associated with HNPCC regardless of age CRC with high MSI CRC <50 yrs in at least 1 first degree relative CRC in 2 first or second degree relatives |
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lynch
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AD
80% penetrant MMR genes |
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How often MSI in sporadic tumors ?
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10-15%
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MLH1 and MSH2
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90% families with detectable mutation
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American founder mutation
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MSH2 - del exons 1-6
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MSH6
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30% less risk for colon cancer
More frequent in famîlie with predominance of èndometrial cancer |
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PMS2
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Low penetrance in heterozygous, homozygous PMS2 deficièncy (recessive)
Severe phenotype: early onset CRC, duodenal can , leukemia, lymphoma , childhood braintumors (astrocytomas, global stomps, primitive neuroectodoermal tumorß ) |
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Familial CRC Type X
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45% families that meet the àmsterdam criteria that do not have a mutation or MSI
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muir - torre syndrome
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*sebaceous carcinoma /adenomas
Keratocarcanthomas |
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turcot's syndrome
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Rare
Multiple colorectal adenomas and primary brain tumors APC: mutations with medulloblastomas MMR ass with glioblastomas |
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Most common Renal Carcincoma
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Clear cell: 70-80%
papillary: 10-15% Chromophobe- 3-5% Hereditary usually multifocal, bilateral, <60 |
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Renal Cancer Susceptibility Syn
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VHL
HPRC Birt Hogg Dube Hereditary Leiomyomatosis and Renal Cell Cancer |
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VHL
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AD with vascular tumors* ANGIOBLASTOMAS, retinal angiomas, pulmonary angiomas, liver hemangiomas, renal cell carcinoma
20% de novo, genetic testing almost 100% testing >90% penetrance mean age dx is 25 yrs (as early as 5 years) Hemangioblastomas (benign)- 60-80% patients, cerebellum, retinal, spine, can cause symptoms Endolymphatic sac tumors- inner ear structure, 10% patients, can have tinnitis to standard screening - Clear cell carcinoma (often bilateral and multifocal), - Pheochromocytoma- produce noradrenaline (norephinepherine), 20% patients, usually bilateral |
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VHL types and risk of tumor types
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hh
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hh
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HB RCC PHEO
1 high high low full deletions, 2A high low high missense mutations (Tyr98His, Tyr112 His) 2B high high high partial gene deletions, nonsense mutations and missense mutations 2C No No High missense mutations Ser80Leu, Val84Leu, Leu188Val |
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Screening for VHL
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MRI of brain and spine starting at 11
Opthamological exam (retinal specialist) -annual starting in early childhood (before age 5) -variable recommendations to increase surveillance Annual/semi annual contrast CT or MRI starting in childhood -renal cancer are watched until 3 cm - pancreatic cysts, neuroendocrine tumors- - pheos Biochemical screening starting at age 5 |
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Hereditary Papillary REnal carcinoma
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-bilateral, multifocal papillary renal ca
50-70 onset kidney only affected activation of proto-oncogene c-MET |
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Birt-Hogg Dube
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-renal cell carcincoma
-fibrofolliculomas -pulmonay cysts and spontaneous pneumothorax -gene BHD-, protein folliculin AD |
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Type of Renal Tumors with Birt Hogg Dube
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Chromophone, hybrid chromophobe
oncocytomas,- benign tumor with renal collecting duct -often bilateral and multiple |
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HLRCC
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cutaneous leiomyomata-skin tumors of smooth muscle cells
78% have it -Uterine leiomyomata (fibroids) -Renal tumors 10-16% -usually solitary -Often type II papillary - collecting duct cancer - occasional clear cell AD, gene FH (fumarate hydratase |
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NF1
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AD, most common 1:3000
half de novo ~80% develop neurofibromas |
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Diagnostic Criteria of NF1
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2 or more of the following:
->6 cal over 5 mm pre puberty individuals over 15 mmm in post pubertal -two or more neurofibromas of any type or one plexiform -axillary or inguinal freckling -optic glioma -two or more lisch nodules -sphenoid dysplasia/pseudoarthrosis -1st degree relative with NF |
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NF Manifestation Frequency
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CAO
Freckling Dermal neurofibromas learning disabilities 30-65% Vascular dx Pheos (5-7%) plexiform neuro- gliomas- 15% of children, <6 yrs 1/2-1/2 symptomatic, bilateral optic glioma highly suspicious, |
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NFLike Syndrome
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CAL, axillary freckling
-no lisch nodules, Neurofiborms, noonan-like dysmorphology dev delay SPREAD1 gene |
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Clinical Management NF1
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Initial: Phy exam, opty and slip lamp exam, dev assessment,brain MRI
Subsequent: blood pressure measurement eye exam annual eye exam, dev assessment, follow up |
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NF2
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AD, 1:60,000, multiple tumors, *vestibular schwannomas*, meningiomas, gliomas, ependyomas,
-onset 18-34 (range birth-70) -almost all develop bil vestib swan by age 30 (tinnitis, loss of balance, numbess, impinge brain) -2/3 develop spinal tumors - Neuropathy (polio like illness), polyneuropathy -cataracts 60-80%, *Juvenile posterior subscapular lenticular opacities) -skin schwannomas, 70% of NF2 -MERLIN gene, 50% de novo |
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Diagnostic criteria for NF2
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Main criteria: bilateral VS, or family hs NF2 plus unilater VS, or combo of any of the omas
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Screening for NF2
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Annual:-optho exam, neuro exam, audio exam (with BAERS)
-10-12: cranial MRI, spinal MRI every 1-3 yrs |
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Schwannomatosis
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-Multipe cutaenous and spinal schwannomas, tumors of pero
NOT vestibular -AD, can be due to NF2, SMARCB1, IGLC1,INIF |
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Tuberous Sclerosis Complex
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Skin: *hypomelanotic macules*, *facial angiofibromas*, shagreen patches, ungual fibromas
Brain: cortical tubers, subependymal nodules, giant cell astrocytomas, seizures, Renal: angiomyolipmas, cysts Cardiac: rhabdomyoma Lymphangiomyomatosis (LAM) -proliferation of smooth muscle tissue into the lung (women only) TSC1 - Hamartin , TSC2 - ruberin (50/50%, 15-20% in sporadic, 80-95% TSC2) *shagreen patch* 50% normal intelligence, 30% severly cognitive impairs 70-89% seizures, *cortical tubers*- cells that dont differentiated into neurons and glial cells |
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Renal Involvement TSC
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-55% at age 7, 80% at age 11
-Angiomyolipoma- benign renal tumors renal cysts -renal cancer- usually clear cell |
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TSC2 and PKD1 contiguous gene
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deletions in ch 16, sever renal cystic phenotype
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Thyroid Cancer
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1.8% non-skin cancer
80-90 % well differ (90% papillar, 10% follicular) 5-10 medullary 1-2 anaplastic 1-2lymphoma |
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Medullary Thyroid Cancer
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10% of all thyroid
-20% 2A, MEN2B~ 2%, FMTC~2% |
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MEN2 gene?
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-RET proto-oncogene on ch 10
- mutated RET gene remains activated ---> tumorigenesis -AD -different gens different symptoms ANY PATIENT WITH MEDULLARY THYROID CANCER=RET TESTING ( no longer use calcitonin, use genetic testing) |
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MEN2 endocrinopathies
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medullary thyroid -100%
pheo - 50% hyperpara- 10-20% |
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MEN2B
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Pheos, ganglioneuromas, colonic issue, marfanoid habitus, skeletal abnormalitie,
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RET mutation testing
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-calcitonin levels no longer useful
-important to know what laboratory test does -* c-cell hyperplasia on pathology suggestive of RET |
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Prophylactic thyroid surgery
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- level 3 mutations (MEN2B) first 6 months of life
-Level 2 (thyroidectomy before age 5) Level1 : before 10 |
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Pheo in MEN2
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generally made after MTC, bilateral (mostly adrenal)
dx in 30's -screen before any surgery, -annual biochemical screening |
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MEN1 Cancers
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Parathyroid tumors, pituitary tumors, endocrine tumors of the GEP tract, carcinoid tumors, adrenocortical tumors
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MEN1 diagnostic criteia
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two or more endocrine tumors that are parathyroid, GEP tract tumors
AD, |
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Paragangliomas
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tumors in endocrine tissue
sympathetic---> secrete, retroperitoneal parasympathethic - non-secretory parasympathetic paragangliomas-head and neck region (biochemically silent) |
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Pheos
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rare
adrenal medulla hypersecrete catecholamines- episodic sweating, blood pressure increase, anxiety, palpatations, weight loss, need to screen due to risk of stroke |
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Genetic Syndromes with Pheo/PGL
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PGL (SDHD, C, B) Carney triad, VHL, MEN2, NF1,
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PGL-1
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Head and Neck paragangliomas
sometimes pheos AD condition maternally imprinted SDHD D for Dad |
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PGL3
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SDHDC gene
EXCLUSIVELY Head and Neck |
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PGL4
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SDHB,
head and neck para extra adrenal pheos adrenal pheos (50% malignant) dx in 30-50's B for BAD |
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Familial Melanoma
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-1-2% affected, most sporadic
-familial in 5-10% CDKN2A, CDK4 |
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Familial Melanoma Genetic Testing?
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> or equal 3 primary
families with one invasic or two or more cases or melanoma or pancreatic cancer |
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FAMMM
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Familial Malignant Melanoma Mole Syndrome (FAMMM)
germline mutations in CDKN2A, 40% hereditary melanoma 30-40's diagnosis -pancreatic cancer risk by age 80 (25% risk) |
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Other genes with familial melanoma risk
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p14ARF
CDK4 MC1R (red hair freckle phenotype) |
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Familial Melanoma Management of Cancer Risk
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derm examinations, start at 10, monthly skin checks, sun protective behaviors, pancreatic screening
ABCD warning signs of melanoma |
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Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
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Rare AD (1/70,000)
high risk for many basal cell carcinomas (100's) PTCH gene 30% cases de novo |
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NBCCS Diagnostic Criteria
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-Two major features of NBCCS and one minor feature
-Major features: multiple bCC, increased calcium deposits on skull, jaw keratocysts, two or more pits on palms of hands, Minor: medullloblastoma in childhood, macrocephaly, cleft lip/palate, bifid ribs, extra fingers/toes, eye probs, ovarian fibroms |
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XP
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Xeroderma Pigmentosum
-AR -diagnostic testing to DNA damage is to test cell response -extreme photosensitivity - endonuclease activity -cellular hypersensitivity -premature skin aging -many cancers: BCC, SCC, MELANOMA, -1st skin cancer at age 8 |
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AT
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ATM, AR
Immunoblotting is more sensitive than genetic testing Serum AFP increased in radiosensitivy asay Immunodeficiency progressive cerebellar ataxia (age 1-4) Telangiectasia enhanced sensitivity to radiation increased risk malignancy (leukemia lymphoma) |
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Fanconi Anemia
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60-75% physical manifestations: short stature radial malform
progressive bone marrow failure (thrombocytopenia, leukopenia age 8) Myelodysplastic syndrome or AML Solid tumors - head/neck, esophagus, cervix liver -Cells show hypersensitivity to DNA damaging agents like mtomycin C or diepoxybutane (DEB) |
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Retinoblastoma
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Pediatric malignant tumor of the eye (retina)
Unilateral and unifocal RB 60% affected children -Bilateral RB -40% of affected children -mean age dx = 15 months RB one gene- 90% mutations found AD positive family hx Neg. family hx: unifocal RB 15% have RB1 mut Other tumors: pinealoma, osteosarcomas, soft tissue sarcoms, melanoma, risk increased in patients who receive high does external beam radiation |
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Wilms Tumor
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MOST common renal tumor in children
family hx in 1-2% of cases FWT1 and fWT2 -overgrowth syndromes: beckwith weidemann, isolated hemihyrophy |
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Beckwith-Wiedemann
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Macroglossia, macrosomia, malignancies (8% before age 8)
-Wilms tumor, hepatoblastoma, Neuroblastoma, rhabdomyosarcoms -omphalocele and abdominal wall defects -neonatal hypoglycemia ear creases/pits |
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Genetic Causes of Beckwidth
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DMR2 Loss of Methylation (50%)
Gain of Methylation DMR1(2-7%) Paternal UPD (20%) CDKNIC (10%) |
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Oncogenes
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- a mutant allele of a protooncogene
-faciliate malignant transformation by stimulating proliferation or inhibiting apoptosis -make proteins in signaling pathways for cell proliferation -growth factos |
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Examples of Oncogenes
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RET MET RAS
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Gatekeeper TSG
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-block tumor development by regulation the transition of cells through checkpoints
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Examples of Gatekeeper TSG
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RB1
TP53 VHL APC |
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Caretaker TSG
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protect integrity of genome
make proteins responsible for detecting and repairing mutations |
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Examples of Caretaker TSG
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MLH1, MSH2, BRCA1, BRCA2
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Chronic Myelogenous Leukemia
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-Philadelphia chromosome
-translocaion of ch 9 and 22 ABL and BCR gene sequences causes leukemia |
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Burkitt Lymphoma
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B-cell tumor of the jaw
-common in children in equatorial Africa -MYC proto-oncogene translocated from normal position to 8;14 translocation |
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Follicular B-cell Lymphoma
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BCL2 gene activation by t(14;18) translocation
inhibits normal apoptosis |
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Two-Hit Model
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Inherit one hit and second hit gives you cancer
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CYP1A
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High inducibility allele
increases risk for lung cancer |
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Follicular B cell lymphoma
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First aopotocic gene in cancer
bCL 2 immuno goblin chains |
