Cancer Genetics II
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| Inheritance for FAP | AD with high penetrance (50% risk by 33yrs)
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| De novo rate for FAP | 15-30%
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| FAP onset | Adenomatous colonic polyps begin in childhood to adolescence
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| 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%)
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| 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
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| Attenuated FAP | mutations on 5' or 3' ends of gene
fewer polyps and age of onset of CRC
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| APC mutations found in ___________ | 10-15% of heptablastoma patients
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| 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
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| Management of FAP | colonscopy (age 10) > coloctemy (late teens/20s) > GI endoscopy follow-up; and annual thyroid exam
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| 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
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| 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)
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| JPC overlaps with | hereditary hemorrhagic telangiectasia (HHT): SMAD4 in overlap pts, chronic epistaxis, pulmonary AVMs
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| Peutz-Jeghers syndrome (PJS) presentation | pigmented spots on lips, buccal mucosa and GI tract, hamartomas of the small and large bowel, INTUSSUSCEPTION
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| Peutz-Jeghers syndrome gene and mutation spectrum | STK11
50% deletions
45% truncating
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| 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
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| HNPCC/Lynch syndrome | AD CRC w/out polyposis assoc/ endometrial ca, bile duct, ovarian, ureteral and gliomas
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| Lynch syndrome penetrance | ~70% lifetime risk of CRC
50-70% endometrial cancer
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| 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+)
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| Risk factors of CRC | general pop = 6%
personal history of CRC = 15-20%
IBD = 15-40%
HNPCC = 60-80%
FAP = >95%
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| CRC genetics | 85% mut and LOF of APC (1% germline)
15% MSI (13% MLH1 promoter silencing, 2% germline MMR mut)
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| MLH1 promoter silencing do/do not respond to 5-Fluoro-uracil | do not
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| Turcot syndrome presentation | assoc of brain tumors and colon polyps/cancer in childhood
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| Dominant forms of Turcot | FAP + medulloblastoma
HNPCC + glioblastoma
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| 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
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| Age of onset w/ MLH1/MSH2 mut | 1st tumor = 3.5 yrs; leukemia = 11yrs; gliomas = 4 yrs; HNPCC assoc tumors = 6yrs
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| Age of onset w/ MSH6/PMS2 mut | 1st tumor = 9yrs; leukemia = 16yr; gliomas = 32yrs; HNPCC assoc tumors = 35yrs
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| Multiple Endocrine Neoplasia 1 (MEN1) tumor spectrum | parathyroid, pancreatic islet cell tumors, anterior pituitary hyperplasia; Zollinger-Ellison syndrome
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| MEN1 +ve carriers biochemical screen | prolactin (5yo)
fasting total serum calcium (8 yo)
fasting serum gastrin (20yo)
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| MEN1 +ve carriers imaging screen | Head MRI (5yo)
abdominal CT/MRI (20yo)
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| Genetic predisposition contribution to breast cancer | 5-10%
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| Her2+ BrCa treated w/ | Trastuzumab
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| ER-/PR-/HER2- are likely to have mutations in which genes | BRCA1
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| 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)
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| 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
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| BRCA1 (17q21) mutation spectrum | most are frameshift/nonsense (LOF)
rare missense in ring finger and BRCT domain
deletions/rearrangements (2-5%)
NONE in sporadic
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| 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
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| BRCA1/2 AJ founder mutations | BRCA1 (185delAG and 5382insC)
BRCA2 (6174delT)
carrier freq (all) 2.4% - resp for 50% of AJ BRCA families
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| VUS rate in BRCA1/2 | 5-10%
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| 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
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| 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
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| Cancer risk for BRCA1 | female breast cancer: 50-85%
male breast cancer: <1%
ovarian cancer: 15-40%
prostate cancer: 8-16%
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| 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%
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| Prophylactic salpingo-oopherectomy success | 90% reduction in ovarian risk
50% reduction in br ca (esp if done 30-40yo)
includes resection fallopian tube resection
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| PARP (poly ADP ribose polymerase) inhibitors (olaparib) as treatment for __? | BRCA1/BRCA2/Fanconi mutant tumors
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| 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)
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| SUFU mutations | give medulloblastoma w/out full Gorlin syndrome
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| 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
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| 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)
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| 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
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| Birt-Hogg-Dube syndrome presentation and genetics | chromophobe/oncocytic RCC, benign fibrofolliculomas, colonic polyps, medullary thyroid cancer, spontaneous pneumothorax;
BHD tumor suppressor gene
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| 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
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| 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)
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| Dyserkatosis congenita genes | Telomere related genes
DKC1 (XLR)
TINF/TIN2, TERC, TERT (AD)
TERT/NHP2/NOP10 (AR)
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| 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
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| Genes in AR disorders | involved in either DNA repair or checkpoint repsonse
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| onset of AR disorders | often in childhood
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| AR cancer syndrome in AJ | Bloom
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| Ataxia Telangiectasia presentation | Ataxia, telangiectasias, immunodef, lymphomas/leukemias +/- solid tumors
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| Cells are sensitive to ionizing radiation in ___ | Ataxia Telangiectasia
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| AT diagnosis | elevated AFP
increased radiation sensitivity on clonal assay
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| 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
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| 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)
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| FA - congenital anomalies | skeletal: radial ray, hip, vertebral,
skin hypo/hyperpigmentation, short stature, microphthalmia, microcephaly, renal: unilateral aplasia hypoplasia horseshoe, hypogenitalia
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| FA cellular phenotype (lymphoblasts and fibroblasts) | increased sensitivity and chromosomal breakage after exposure to diepoxybutane (DEB) and Mitomycin C (MMC)
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| 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
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| Genes in both FA and Hereditary BC | BRCA2/D1
BRIP1/J
PALB2/N
ATM
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| Bloom presentation and genetics | small, stature, phosensitive rash, immuno deficiency, multiple tumors including leukemia/lymphoma and solid tumors
BLM gene (15q26.1)
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| Werner presentation and genetics | premature aging, cataracts, diabetes, atherosclerosis, soft tissue sarcomas, skin cancers
WRN gene (8p11)
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| Rothmund Thomson presentation and genetics | Poikiloderma rash, sparse hair, radial ray defects, cataracts, osteosarcomas and skin cancers
RECQL4 gene (8q24.3)
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| RAPIDILINO/Baller-Gerold presentation and genetics | Osteosarcoma
RECQL4 mutation
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| RecQ Helicase disorders (AR) | Bloom
Werner
Rothmund Thomson
Baller-Gerold (RAPIDILINO)
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| important feature in Rothmund Thomson (RTS) | poikiloderma- rash starts in infancy on cheeks spreads to extremeties (but not on thorax and buttocks)
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