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cancer_gen2_acmg

Cancer Genetics II

TermDefinition
Inheritance for FAP AD with high penetrance (50% risk by 33yrs)
De novo rate for FAP 15-30%
FAP onset Adenomatous colonic polyps begin in childhood to adolescence
Extracolonic Manifestations of FAP (refered to Gardner syndrome) Desmoid (fibroblast) tumors (often abdominal); osteomas of jaw, skull, bones; epidermoid cysts on face or trunk; CHRPE (asymptomatic); pediatric hepatoblastoma (0.5-1%); thyroid cancer (1%), medulloblastoma (<1%)
Gene and mutation spectrum in FAP APC gene: ~80 truncating mut, 5-10% deletions; small number of missense *exon 15 mutations assoc. with extracolonic symptoms
Attenuated FAP mutations on 5' or 3' ends of gene fewer polyps and age of onset of CRC
APC mutations found in ___________ 10-15% of heptablastoma patients
Hepatoblastoma and desmoid tumors arise by somatic activation mutation of beta catenin (exon 2 of CTNNB1 gene) OR germline inactivating mutations in APC *both upregulate beta catenin signalling
Management of FAP colonscopy (age 10) > coloctemy (late teens/20s) > GI endoscopy follow-up; and annual thyroid exam
MUYH/MYH Assoc Polyposis inheritance, presentation, genetics AR >100 polyps 2 common MUTYH mutations: Y165C (hom=46yrs mean onset), G382D (hom=58yrs), cmpd het (52yrs) MUTYH encodes base excision repair protein
Juvenile Polyposis Coli (JPC) presentation and genetics bleeding, rectal prolapse, pain, childhood onset of hamartomas colonic polyps BMPR1A and SMAD4 in ~50% of pts PTEN ~1-2 (severe PTEN + BMPR1A) CRC (50% with mean onset 43yrs with more having SMAD4)
JPC overlaps with hereditary hemorrhagic telangiectasia (HHT): SMAD4 in overlap pts, chronic epistaxis, pulmonary AVMs
Peutz-Jeghers syndrome (PJS) presentation pigmented spots on lips, buccal mucosa and GI tract, hamartomas of the small and large bowel, INTUSSUSCEPTION
Peutz-Jeghers syndrome gene and mutation spectrum STK11 50% deletions 45% truncating
Peutz Jeghers syndrome penentrance lifetime risk is 81% GI cancers -66% breast cancer - 32% in women benign ovarian sex-cord tumors, Sertoli-cell testicular tumors
HNPCC/Lynch syndrome AD CRC w/out polyposis assoc/ endometrial ca, bile duct, ovarian, ureteral and gliomas
Lynch syndrome penetrance ~70% lifetime risk of CRC 50-70% endometrial cancer
HNPCC gene and mutation spectrum MSH2 and MLH1 (80-90% of families) EPCAM/TACSTD1 ex8/9 = read pass thru = MSH2 methyl=turned off MSH6 (CRC in 44% in males and 22% in females) PMS2 (lower penetrance) MSI (five msrkers (stable=0, low=1, high=2+)
Risk factors of CRC general pop = 6% personal history of CRC = 15-20% IBD = 15-40% HNPCC = 60-80% FAP = >95%
CRC genetics 85% mut and LOF of APC (1% germline) 15% MSI (13% MLH1 promoter silencing, 2% germline MMR mut)
MLH1 promoter silencing do/do not respond to 5-Fluoro-uracil do not
Turcot syndrome presentation assoc of brain tumors and colon polyps/cancer in childhood
Dominant forms of Turcot FAP + medulloblastoma HNPCC + glioblastoma
AR Turcot presentation and genetics brain and colon ca, atypical cafe au lait spots and axillary freckling MSH2, MLH1 - most severe PMS2 - most common MSH6
Age of onset w/ MLH1/MSH2 mut 1st tumor = 3.5 yrs; leukemia = 11yrs; gliomas = 4 yrs; HNPCC assoc tumors = 6yrs
Age of onset w/ MSH6/PMS2 mut 1st tumor = 9yrs; leukemia = 16yr; gliomas = 32yrs; HNPCC assoc tumors = 35yrs
Multiple Endocrine Neoplasia 1 (MEN1) tumor spectrum parathyroid, pancreatic islet cell tumors, anterior pituitary hyperplasia; Zollinger-Ellison syndrome
MEN1 +ve carriers biochemical screen prolactin (5yo) fasting total serum calcium (8 yo) fasting serum gastrin (20yo)
MEN1 +ve carriers imaging screen Head MRI (5yo) abdominal CT/MRI (20yo)
Genetic predisposition contribution to breast cancer 5-10%
Her2+ BrCa treated w/ Trastuzumab
ER-/PR-/HER2- are likely to have mutations in which genes BRCA1
Breast Cancer syndromes Breast-Ovarian (BRCA1>BRCA2);Li-Fraumeni (p53 onset at 32yo); PJS (STK11 32% by 60yo); Cowden's syndrome (PTEN);RAD51C (in br & ovarian); Hered diffuse gastric ca and lobular breast ca (CDH1); Moderate risk (RR-2) (CHEK2 1100delC, PALB2, BRIP1, ATM hets)
Cowden syndrome (PTEN Hamartoma syndrome) cancer spectrum Breast (~30 lt risk); Thyroid (~10% lt risk); Adult Lhermitte-Duclos disease (cerebral hamartomas), cerebral dysplastic gangliocytoma; trichilemmomas, acral keratoses, papillomatous lesions, mucusal lesions
BRCA1 (17q21) mutation spectrum most are frameshift/nonsense (LOF) rare missense in ring finger and BRCT domain deletions/rearrangements (2-5%) NONE in sporadic
BRCA2 (13q12) mutation spectrum most are frameshift/nonsense NONE in sporadic ca *significant predisposition to male breast cancer and pancreatic cancer is both m and f
BRCA1/2 AJ founder mutations BRCA1 (185delAG and 5382insC) BRCA2 (6174delT) carrier freq (all) 2.4% - resp for 50% of AJ BRCA families
VUS rate in BRCA1/2 5-10%
BRCA1/2 protein functions involved in response to DNA damage and phosph by ATM; BRCA1 interacts with Rad51 DNA repair prot in hom recomb; BRCA2 interacts with Rad52 PALB2 both are PARP inhibitors
Risk Prediction Models for Breast Cancer Gail Model: risk for someone of 'average risk'; Claus tables: risk based on FHx BRCAPro: likelihood that genetic testing will yeild BRCA1/BRCA2 mutation
Cancer risk for BRCA1 female breast cancer: 50-85% male breast cancer: <1% ovarian cancer: 15-40% prostate cancer: 8-16%
Cancer risk for BRCA2 female breast cancer: 50-85% male breast cancer: 6% ovarian cancer: 15-20% prostate cancer: 8-16% pancreatic cancer: 1.5-2%
Prophylactic salpingo-oopherectomy success 90% reduction in ovarian risk 50% reduction in br ca (esp if done 30-40yo) includes resection fallopian tube resection
PARP (poly ADP ribose polymerase) inhibitors (olaparib) as treatment for __? BRCA1/BRCA2/Fanconi mutant tumors
Gorlin syndrome (Basal Cell Carcinoma) presentation and genetics multiple nevoid basal cell carcinomas (in teens), odontogenic jaw cysts, bifid ribs, prominent forehead, calcification of falx cerebri, plantar and plamar pits, 4-5% 4isk of medulloblastoma; due to PTCH (patched) gene (sometimes result only in BCC)
SUFU mutations give medulloblastoma w/out full Gorlin syndrome
Pheochromocytomas and Paraganliomas genetics 40-50% have germline het mutation in succinate dehydrogenase subunits (SDHB/D/C/A, SDHAF2) SDHD imprinted, affected when inherited from father SDHB assoc w/ malignant pheochromocytoma VHL RET Rarely NF1
Familial Isolated Pituitary Adenomas pituitary adenomas expressing GH, PrL, TSH, ACTH or non-functioning, onset 20-24 yrs, AD (reduced pen), AIP gene (90% seq, 10% del/dup)
Renal Cell Cancer genes VHL - clear cell histology balanced translocation inv chr3 - clear cell c-Met activating mut - papillary renal carcinoma fumarate hydratase (FH) - hereditary leiomyomatosis RCC (AD) Birt-Hogg-Dube syndrome- chromophobe/oncocytic
Birt-Hogg-Dube syndrome presentation and genetics chromophobe/oncocytic RCC, benign fibrofolliculomas, colonic polyps, medullary thyroid cancer, spontaneous pneumothorax; BHD tumor suppressor gene
Dyserkatosis congenita presentation and genetics clinical triad (nail dystrophy, oral leukoplakia, abnormal skin pigmintation), hypoplastic bone marrow; due to dysfunctional telomeres (telopathy) <1%ile in lymphocyte using flow
Dyserkatosis congenita related mortality mean age =30s bone marrow failure/immunodef 60-70%, pulmonary complication 10-15%; malignancy 20% (AML and head and neck ca in young adults)
Dyserkatosis congenita genes Telomere related genes DKC1 (XLR) TINF/TIN2, TERC, TERT (AD) TERT/NHP2/NOP10 (AR)
Pleuro Pulmonaryblastoma (PPB) presentation and genes rare dev tumor disorder w/ lung cysts and PPB, may include multicystic goiter, cystic nephroma, ovarian sertoli-leydig-type tumors, wilms tumor, rhabdomyosarcoma, intraocular medulloepithelioma; AD (incomplete, var express) DICER1 inactivatin mut
Genes in AR disorders involved in either DNA repair or checkpoint repsonse
onset of AR disorders often in childhood
AR cancer syndrome in AJ Bloom
Ataxia Telangiectasia presentation Ataxia, telangiectasias, immunodef, lymphomas/leukemias +/- solid tumors
Cells are sensitive to ionizing radiation in ___ Ataxia Telangiectasia
AT diagnosis elevated AFP increased radiation sensitivity on clonal assay
AT genetics ATM gene - damage checkpoint prot, ATM phophorylates prot encodes susceptibility genes (p53, BRCA1) Mut in ATM (AD) include truncating alleles and missense (function domains) Het carriers have 2X risk of breast cancer
Fanconi Anemia presentation and genetics Congenital anomalies, bone marrow failure-pancytopenia 5-10yo, malignancy (myelodysplasia/AML, head neck and GU tumors) AR syndrome (14 different complementation groups): FA-A,B (X-linked), C, D1(BRCA2), D2, E,F,G,I,J(BRIP1),K,L,M,N(PALB2), P(SLX4)
FA - congenital anomalies skeletal: radial ray, hip, vertebral, skin hypo/hyperpigmentation, short stature, microphthalmia, microcephaly, renal: unilateral aplasia hypoplasia horseshoe, hypogenitalia
FA cellular phenotype (lymphoblasts and fibroblasts) increased sensitivity and chromosomal breakage after exposure to diepoxybutane (DEB) and Mitomycin C (MMC)
BRCA2 mut in FA biallelic mut BRCA2 have severe form of FA (FA-D1) presentation: congen anomalies, very early onset AML, MDblastoma and Wilm's tumor
Genes in both FA and Hereditary BC BRCA2/D1 BRIP1/J PALB2/N ATM
Bloom presentation and genetics small, stature, phosensitive rash, immuno deficiency, multiple tumors including leukemia/lymphoma and solid tumors BLM gene (15q26.1)
Werner presentation and genetics premature aging, cataracts, diabetes, atherosclerosis, soft tissue sarcomas, skin cancers WRN gene (8p11)
Rothmund Thomson presentation and genetics Poikiloderma rash, sparse hair, radial ray defects, cataracts, osteosarcomas and skin cancers RECQL4 gene (8q24.3)
RAPIDILINO/Baller-Gerold presentation and genetics Osteosarcoma RECQL4 mutation
RecQ Helicase disorders (AR) Bloom Werner Rothmund Thomson Baller-Gerold (RAPIDILINO)
important feature in Rothmund Thomson (RTS) poikiloderma- rash starts in infancy on cheeks spreads to extremeties (but not on thorax and buttocks)
Created by: amrs
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