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cancer_gen2_acmg
Cancer Genetics II
| Term | Definition |
|---|---|
| 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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