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tumors assoc with somatic Rb mutation
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retinoblastoma, osteosarcoma, carcinoma of the breast, colon, and lung
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Defects in DNA repair system
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mismatch repairnucleutide excision repairdiseases with defect in DNA repair by homologous recombination
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TGF-B receptor
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fxn in growth inhibitiontumors assoc with somatic mut: carcinoma of colon
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p16 (INK4a)
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fxn is to regulate cell cycle by inhibition of cyclin dependent kinases;
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oncogenes cause ? without binding to the growth receptor
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persistent tyrosine kinase activity
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TS genes located on cell surface
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TGF-B receptorE-cadherin
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GAP
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functions as the brakes and prevents uncontrolled ras activity
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point mutation in BRAF
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detected in more than 60% of melanomas and 80% of benign nevi
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HST 1 and INT 2
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encode homologs of FGFs; activated in GI and breast tumors. bFGF is expressed in human melanomas.
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TS genes located on inner plasma membrane and cytoskeleton
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NF1NF2
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NER
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XP--pt at increased risk of skin cancer when exposed to UV rays. UV light causes cross linknig of pyrimidine residues
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amplification of CDK4 gene
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melanomas, sarcomas, and glioblastomas
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tumor suppressor genes located in the cytosol
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APC/Beta cateninPTENSMAD2 and SMAD4 (DPC4)
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tumors assoc with somatic mutation of p16
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pancreatic, breast, and esophageal
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cyclin D genes
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overexpressed/amplified in many carcinomas, eg breast, esophagus, and liver. translocation is seen in subsets of lymphoma (mantle cells)
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RAS
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cause overexpression of transforming growth factor (TGF-a), which is related to EGF and is expressed in carcinomas such as astrocytomas and hepatocellular carcinoma
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NF1
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neurofibromin is protein prod; fxn is inhibition of RAS signal transduction and p21 cell cycle inhibotor; somatic mut: neuroblastomas; inherited mut: neurofibromatosis type 1 and sarcomas
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NF2
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merlin is protein prod; fxn is cytoskeleton stability; somatic mut: schwannomas and meningiomas; inherited mut: NF type 2, acoustic schwannomas and meningiomas
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tumors assoc with inherited mutations of Rb
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retinoblastoma, osteosarcoma, and soft tissue sarcomas
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knudson "two hit" hypothesis of oncogenesis
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explains familial and sporadic occurences; in hereditary cases, one hit inherited from affected parent, and second hit in one of many retinal cells. in sporadic cases, both hits occur in retinal cells. both alleles of Rb locus must be inactivated for development of retinoblastomas
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diseases with defect in DNA repair by homologous recombination
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AR disorders: ataxia-telangectasia, Bloom syndrome, and Fanconi anemia
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tumor suppressor genes located in the nucleus
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p53RbWt-1p16KLF6
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mutation that dysregulates activity of cyclins and cyclin-dependent kinases
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favor cell proliferation
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mismatch repair (spell checkers)
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microsatellite instability is hallmark; (hereditary nonpolyposis cancer syndrome)- cancers of cecum and proximal colon (pts <50yrs); also assoc with endometrial and ovarian cancers; germ line mutation of MSH2 (2p16) and MLH1(3p21) account for 30% of cases
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N-myc amplification
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neuroblastomas
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myc dysregulation
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noted in Burkitt's lymphoma (t8;14)
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WT-1
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on 11p13; fxn in nuclear transcription; associated tumors: wilm's tumor (nephroblastoma)
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PTEN
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phosphatase and tensin homolog located on 10q23; activity casues cell cycle arrest by increasing txn of p27 cip/kip cell cycle inhibitors and apoptosistumors assoc with somatic mut: endometrial and prostate
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tumors assoc with inherited mutation of p53
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Li-fraumeni syndrome (multiple carcinomas- breast and brain) and sarcomas
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RET
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a receptor tyrosine kinase that undergoes oncogenic conversion via mutation and gene rearrangement. it is a receptor for glial cell line-derived neurotropic facotr. pt mutation is assoc with inherited MEN 2A and 2B and familial medullary thyroid carcinoma
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L-myc amplifciation
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small cell carcinomas of the lung
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tumors assoc with somatic mutation of APC
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carcinomas of stomach, colon, pancreas, melanomas
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HGF and its receptor c-MET
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overexpressed in follicular thyroid carcinoma
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tumors assoc with somatic mutation of p53
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most human cancers including lung, colon, and breast
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point mutation of c-FMS gene
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encodes CSF-1 receptor-- has been detected in myeloid leukemia.
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ras is also invovled in...
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cell cycle regultaion. it controls the levels of CDKs by unknown mechanisms
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c-abl
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non receptor associated tyrosine kinase that has activity that is dampened by negative regulatory domains. in CML and some ALL types, activity is unleashed bc the c-abl is translocated from normal location on chromosome 9 to the bcr region on 22. bcr-abl has tyrosine kinase activity
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BCL-2
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85% of follicular B cell lymphomas carry a characteristic t(14;18)(q32;q21) translocation which prevents apoptosis. pro apoptotic members of family are Bak, Bax, and Bim
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tumors assoc with inherited mutation of p16:
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malignant melanoma
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ERB-B2 (Her2/neu)
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amplified in 25% of breast cancers, adenocarcinomas of the ovary, lung, stomach, and salivary gland
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evasion of apoptosis
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BCL-2
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E-cadherin
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fxn in cell adhesion; somatic mut: carcinoma of stomach; inherited: familial gastric cancer
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single most common abnormality of dominant oncogenes in human tumors
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mutation in RAS. kras-- pancreatic tumors, colon, and lunghras- bladder and kidney tumorsnras- melanomas and hematologic malignancies
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SJS- oncogene
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encodes beta chain of PDGF, which is a potent mitogen for fibroblasts, smooth muscle cells, and glial cellsastrocytomsa and osteosarcomas produce PDGF like polypeptides. tumors express receptors for PDGF
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SMAD 2 and 4 (DPC4)
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fxn is TGF-B growth inhibitory signal transduction; SMAD4 is inactivated in 50% of pancreatic cancers; 2 is present in some colorectal cancers
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p53 geneguardian of the genome
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located on 17p13.1; over 50% of human tumors contain mutations in this gene; fxn is cell cycle arrest and apoptosis in response to DNA damage;
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APC/Beta catenin
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fxn: inhibition of signal transduction; APC protein downregulates beta catenin. in absence of WNT, APC causes degredation of B cat, thus preventing its accumulation in the cytoplasm. B cat forms complex with TCF in the nucleus (txn factor)
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pt mutation in c-KIT
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encodes the receptor for stem cell factor (steel factor) associated with GI stromal tumors
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BRCA-1 and BRCA-2 Genes
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Individuals who inherit mutations of BRCA 1 and 2 susceptible to breast cancer.Germ line mutation of BRCA-1: breast and ovarian cancerGerm line mutation of BRCA-2: ovary (<BRCA-1) and male breast cancer.10-20% of breast cancers are familial and mutation of BRCA-1 and BRCA-2 account for 80% of familial breast cancer.The mutation is present in < 3% of all breast cancers.
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KLF6
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fxn is to encode txn factor; associated in more than 70% of primary prostate cancer
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Rb
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located on chrom 13q14; germ line mutation and LOH predisposes to cancer; function is to regulate cell cycle;
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tumors assoc with inherited mut of APC
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familial adenomatous polyposis coli/colon cancer
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following translation, c-myc...
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translocated to the nucleus, where it combines with max. the c-myc-max complex binds to E-boxes (DNA sequences) and is a potent txn activator. this activates the txn of growth related genes
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ERB-B1
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EGF receptor gene (EGFR) that is overexpressed in 80% of squamous cell carcinomas of the lung and to a lesser extent in carcinomas in the bladder, GI tract, and astrocytomas.
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