Oncogenes and Tumor Suppressors MCB 5068 November 12, 2013 Jason Weber jweber@dom.wustl.edu
Oncogenes & Cancer
DNA Tumor Viruses Simian Virus 40 p300 prb p53 Large T Antigen Human Adenovirus p300 E1A prb p53 E1B Human Papillomavirus E7 prb p53 E6
Normal Stage 1A Stage 2 Stage 4 Stage 1A: Local <3mm, 95% survival Stage 1B: Local <4cm bulky, 80% survival Stage 2A: Vaginal, 75% survival Stage 2B: Parametrium, 60% survival Stage 3: Side walls of pelvis/kidney, 40% survival Stage 4A: Pelvis, bladder, rectum, 20% survival Stage 4B: Beyond pelvis, 0%
Famous Oncogenes Growth Factors int-2 sis FGF PDGF Growth Factor Receptors erbb-1 fms kit met erbb-2 EGF-R CSF-1R Stem Cell GF-R Hepatic GF-R Heregulin R Cytoplasmic Kinases bcr-abl fes src lck yes Nuclear Proteins ets fos jun myc
The Definition of a Tumor Suppressor Classical Features: Loss of function mutations Targeted allelic loss - Methylation or Deletion Inherited mutations that predispose to cancer Somatic mutation in spontaneous tumors Ability to inhibit transformed cells in vitro Haber & Harlow Criteria: Loss of function mutations in the development of cancer
Familial Cancer Syndromes Li-Fraumeni von Hippel-Lindau p53 VHL Deleted in Pancreas Adenomatous Polyposis Smad4 APC Retinoblastoma Melanoma Rb INK4a/ARF Breast Cancer Cowden Disease Brca1,2 PTEN Wilms Tumor Gorlin WT1 PTCH Nonpolyposis Colon Multiple Endocrine Neoplasia MSH2,MLH1 MEN1 Neurofibromatosis 1,2 NF1,NF2
NF1 Controls Ras Activity Neurofibromatosis identified in 1882 17q11.2 Linkage studies Benign tumors along peripheral & optic nerves Increase risk of: Neurofibrosarcomas Astrocytomas Rhabdomyosarcomas Myeloid leukemias Acts as a Ras-GAP
PTEN Regulates AKT Activity Protein tyrosine phosphatase Mutated in glioma, breast prostate, head&neck, sqamous cell cancers Suppresses AKT activity Converts PIP 3 to PIP 2 Prevents activation of downstream AKT targets
Function of the Wilms Tumor Protein - Most common childhood abdominal cancer - 10 per 1 million children - 90% Survival rate - Only 5-10% bilateral tumors - Zinc finger transcription factor encoded at 11p13-11p15 also implicated: encodes p57kip - WT1 -/- lethal, no kidneys - Two splicing variants One induces cellular proliferation genes Second regulates mrna processing - Binds to a host of cellular factors (p53, p300 etc)
Susceptibility Through BRCA1&2 Mutations BRCA1 & 2 found in complexes with Rad51 Localized to sub-nuclear foci Co-expressed during development Rad51 operates in double-strand DNA breaks by binding ssdna and invading homologous duplex DNA Loss results in the activation of a p53 response p53 -/- or p21 -/- delays death Breast tissue proliferation during development acts as an incubator for amplifying mutated cells
Progression From Normal to Cancerous Transforming and Immortalizing Events - Different for each cell type - Never just a single or double event
Activating the p53 Response
p53 Modifications
The p53 Pathway - There are many ways to affect p53 - Loss of sensory tumor suppressors Overexpression of cellular oncogenes or viral oncogenes Mutation of p53 itself (most common) but not obligatory All result in an inability to correctly halt the cell cycle or eliminate the cell In response to tumorigenic changes
The CDK Inhibitors Overexpression of Cdk4, Cyclin D1 Breast cancer Glioblastomas Head & Neck Cancer Low levels of p27 KIP1 Breast Cancer
Accessing the Cell Cycle Machinery
The INK4a/ARF Locus Fibrosarcomas Lymphomas Gliomas Melanomas Fibrosarcomas Lymphomas Gliomas
Loss of ARF with Retention of INK4a in Cancer A wide variety of tumors lose ARF expression while retaining INK4a Most are through hypermethylation of the ARF promoter Loss of ARF within p53 mutant tumors TUMOR PROGRESSION???? WHY????
NUCLEOLUS Pol I NUCLEOPLASM Pol III 18S 28S 5.8S 5S 5S---L5---NPM NUCLEAR EXPORT ARF 60S
Melanoma: Early Detection is Crucial! There is a direct correlation between the thickness of the melanoma and survival rate. For localized melanoma, melanoma that has not spread beyond the outer layers of the skin at the time of detection, the average five-year survival rate is 96 percent. American Academy of Dermatology http:// www.aad.org/aad/newsroom/melanomfactsheet.htm
Survival curves of 1,528 melanoma patients with lymph node metastases subgrouped by the actual number of metastatic nodes. The correlation is significant (P <.0001). BALCH CM et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the AJCC staging system. J Clin Oncol 19:2001
Melanoma risk factors Fair skinned Lots of moles History of sunburns and sun exposure Family History