PROTOONCOGENES, ONCOGENES, ONCOPROTEINS GROWTH FACTORS SIS (PBGFB) HST1 INT-a (FGF-3) TGFA HGF GROWTH FACTOR RECEPTORS

ERBB1 ERBB2 EGFR FLT3 RET PDGFRB KIT SIGNAL TRANSDUCTION RAS KRAS HRAS NRAS ABL BRAF b-catenin NUCLEAR REGULATORY MYC CMYC NMYC LMYC CELL CYCLE REGULATORS Cyclin D Cyclin E CDK4

Encodes B chain of PDGF. Overproduced in Astrocytoma, osteosarcoma. Cells express PDGFR (Autocrine) FGF homologue. Overexpressed in GI tumors. FGF homologue. Amplified in Bladder, Breast, Melanoma EGF homologue. Overexpressed in Astrocytomas, Hepatocellular carcinoma Overexpressed in Thyroid Cancer EGFR. Overexpressed in 80% squamous cell lung, 50% glioblastoma, 80-100% H/N tumors. HER2/neu, EGFR. Amplified in 25% breast cancers. Point Mutation in tyr-kinase receptor myeloid luekemias (15;17) and CN AML (bad prognosis) Germline inheritance Point Mutation in tyr-kinase receptor MEN2A (extracellular), MEN2B (cytosolic) MEN2A Thyroid, adrenal, parathydroid. MEN2B Thydroid, adrenal. . Overexpression glioma Translocationleukemia Receptor tyr-kinase for stem cell. Point mutation GI tumors (90%) GTP binding domain. Point mutation is most common abnormality of proto-oncogenes in all human tumors (15-20%) Carcinomas of colon, lung, pancreas Bladder tumors, kidney tumors. Hematopoietic tumors. Non-Receptor tyrosine kinase. Translocation from Chromosome 9 in CML, ALL RAS signal transduction. 80% of nuevi, 60% of melanomas. Part of WNT signaling. Point mutation Hepatoblastomas. Overexpression Hepatocellular carcinoma Immediate early response gene. Cyclin D2 is a target. Thousands of binding sites. Overexpression checkpoint bypass (GF+), apoptosis (GF-) Translocated from chromosome 8 in Burkitt lymphoma. Amplified in nueroblastoma On Chromosome 2 Amplified in small cell carcinoma of lung On chromosome 11. Binds CDK4 to phosphorylate RB, allowing G1 S phase transition. Translocated in Mantle Cell (11;14). Amplified in Breast, esophageal cancers. Complexes with CDK2. Expressed late G1. Allows G1S. Expression dependent on E2F family of TFs. Overexpression Breast Cancer. Forms complex with Cyclin D that phosphorylates RB. Amplification, point mutation melanomas, sarcoma, glioblastoma.

TUMOR SUPPRESSOR GENES

TGFb pathway TGF-b receptor E-cadherin

NF1 NF2

APC/b-catenin

PTEN

SMAD2 SMAD4 RB1

TGF is potent inhibitor of proliferation. Receptor is serine-threonine kinase complex of I and II. Phosphorylates R-SMAD SMAD 4 binding CDKI transcription. 100% of pancreatic, 83% of colon has mutation in TGF-b pathway. Mutation in type II colon, stomach, endometrial cancers. Located on 16 q. Expression downreagulated by SNAIL. Mediate epithelial cell adhesion. Connected to bCatenin and actin skeleton intracellularly. Mutation leads to sense of loss of contact. Loss leads to easy disaggregation of cells metastatic spread. Loss key in EMT. Somatic mutation (reduced expression) carcinoma of stomach. Germline Familial gastric cancers. Neurofibromin = GTPase Activator Protein (GAP) Inner surface of PM. Inhibition of RAS. One inherited mutant allele NFM1 (benign neurofibromas and optic gliomas after inactivation of 2nd allele). Can later develop malignant peripheral sheath tumors. Produces Merlin. Member of SWH tumor suppressor pathway. Establishes stable cell-cell junction. Homology with RBC cytoskeletal protein Band 4.1. On cytoskeleton cytoskeltal stability. Germline Mutation in 1 allele bilateral schwannomas. Normal function to inhibit signal transduction. Chromosome 5q21. Mutation unregulated proliferation. Thousands of polyps by 20, increasing malignancy chance. 70-80% of familial colon cancers implicated. Part of WNT pathway. APC downregulates b-catenin by ubiquitination. Signal by WNT stops APC. Bcatenin +TCF upregulates cyclin D1 and c-MYC. Phosphatase and Tensin homologue. Membrane associated phosphatase on chromosome 10q23. Mutated in Cowden syndrome (AD disorder with frequent benign tumors of skin appendages). Frequent in epithelial cancers, particularly breast, endometrium, thyroid. Inhibitor of PI3K/AKT pathway (Prosurvival/growth path) TGF-b pathway. Chromosome 18q21 Binds R-SMAD in TGF-b pathway CDKI expression. Mutation pancreatic cancers. Chromosome 18q21 13q14 Regulation of cell cycle. Protein binds Binds E2F. HPV E7 will bind and release E2F proliferation. Hypophosphorylated binds E2F. Phosphorylation by CyclinD/CDK4 leads to E2F release and p27. Blocker of cell progression from G1S. Child who inherits one mutant allele is heterozygous and normal. Second hit = Loss of heterozygosity (LOH). Retinoblastoma and osteosarcoma. Chromosome 17p13.1 Most common genetic alteration in tumors. 50% of tumors contain mutation. Li Fraumani syndrome = 1 allele lost, 25x increase in risk of cancer. Tumor suppressor gene altered in the majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. p53 is required for the G 1/S checkpoint and is a main component of the G2/M checkpoint. HPV E6 degrades p53. 11p13. Wilms tumor if inactivated. Involved in gonadal and renal differentiation. Regulates mesenchymal to epithelial transition. In adults overexpression can lead to tumorigenesis. Regulation of cell cycle. Blocks CyclinD/CDK4 phosphorylatoin of RB. CDKI. Crucial for induction of senescence. Bladder, head, neck tumors, ALL, cholangiocarcinomas. In cervical cancer, hypermethylation leads to inactivation. Chromosome 17q21. Breast and ovarian cancers, prostate cancers. Involved in homologous recombination repair. Subject to methylation. Chromosome 13q12-13. Fanconi anemia! BRCA1 plus pancreas, bile ducts, stomach, melanocytes. Involved in homologous recombination repair.

p53

WT1 P16/INK4a BRCA1 BRCA2

MOLECULES THAT PARTICIPATE IN APOPTOSIS CD95/Fas Extrinsic death receptor pathway. Activation by FasL leads to trimerization of receptor and cytoplasmic death domains, which attract FADD, which attracts procaspase 8 caspase 3 activation (executioner caspase) and DNA cleavage. Reduced levels antiapoptosis. Under regulation of p53. Along with BAK, directly promote mitochondrial permeabilization, leading to cytochrome C escape and APAF1 activation caspase 9 activation. Inhibited by BCL2. Barrier to mitochondrial permeabilization. Anti-apoptotic. Chromosome 18q21. Follicular lymphoma t(14; 18) Roughly 10-20% of DLBCL. Lead to DNA cleavage and cell death. Apoptosis regulators. Caspase 3 is most important executioner. Caspase 8 active in extrinsic pathway with CD95/Fas. Caspase 9 active in intrinsic pathway with Cytochrome C. Chromosome 17p13.1 Most common genetic alteration in tumors. 50% of tumors contain mutation. Li Fraumani syndrome = 1 allele lost, 25x increase in risk of cancer. Tumor suppressor gene altered in the majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. p53 is required for the G 1/S checkpoint and is a main component of the G2/M checkpoint. HPV E6 degrades p53.

BAX BCL2 Caspases p53

DNA REPAIR GENES MSH2 MLHI ATM BRCA1 BRCA2 Chromosome 2p16 Involved in HNPCC. 30%. Silenced by epigenetic modification in prostate cancers. 3p21. Involved in HNPCC. 30% Ataxia telangiectasia mutated. Germ line mutation. Cant repair DNA damage when ATM is damaged by ionizing radiation. Phosphorylate p53 to pause cell cycle. Chromosome 17q21. Breast and ovarian cancers, prostate cancers. Involved in homologous recombination repair. Subject to methylation. Chromosome 13q12-13. Fanconi anemia! BRCA1 plus pancreas, bile ducts, stomach, melanocytes. Involved in homologous recombination repair.