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Cancer as a genetic chapter 23 select topics and lecture notes What is cancer? Epidemiology statistics Phenotype of the cancer cell Cancer genes Tumor suppressor genes oncogenes How cancer genes do alter a cell’s phenotype? Molecular multi-step process and cancer P53 and Rb genes: specific example Cancer is abnormal cell growth. Lead to TUMOR is NOT = CANCER TUMORS= Neoplasms Cancers however are malignant tumors Benign Some benign tumors may be enlargements without abnormal growth eg. CF A photo of a sweat gland Hidradenoma: fluid filled benight Most cancers fall into one of these groups Carcinomas Sarcomas Leukemias Lymphomas 2009 Estimated US Cancer Deaths* Lung & bronchus 30% Men 292,540 Women 269,800 26% Lung & bronchus Prostate 9% Colon & rectum 9% 9% Pancreas 6% 6% Pancreas Leukemia 4% Liver & intrahepatic bile duct 4% Esophagus 4% Urinary bladder 3% Non-Hodgkin lymphoma 3% Kidney & renal pelvis 3% All other sites 15% Breast Colon & rectum 5% Ovary 4% Non-Hodgkin lymphoma 3% Leukemia 3% Uterine corpus 2% Liver & intrahepatic 25% bile duct 2% Brain/ONS 25% ONS=Other nervous system. Source: American Cancer Society, 2009. All other sites Characteristics of Cancer Loss of contact inhibition Loss of apoptosis Growth in soft agar Tumor growth “in vivo” 2 broad groups of cancer causing genes 1. Tumor suppressor genes 2. Oncogenes 1. Tumor Suppressors Normally requires 2 “hits” Mutations cause loss of function haploinsufficiency Alfred Knudson: 2 hit model of cancer 1. Loss of Heterozygosity Examples of tumor suppressors Retinoblastoma gene (rb) p53 gene Retinoblastoma: Rb gene and Retinal tumor Li-Fraumeni Syndrome autosomal dominant P53 gene and breast cancer bilateral retinoblastoma autosomal dominant Example osteoclasts neutrophils P53 and the bax gene Nobel Prize in 2002 for their discovery of apoptosis Brenner Horvitz Sulston 2. Oncogenes ■ Second group of cancer causing genes ■ Mutations cause a gain of activity ■ Requires only one “hit” 2. Where do Oncogenes originate? Hypothesis of origin of oncogenes Viruses recombine with proto- oncogenes Michael Bishop and Harold Varmus Possible outcomes of recombination virus Proto-oncogenes Control by viral promoter Oncogene mutated in virus mutated by virus In host cell DNA Here are some examples of how tumor suppressors and oncogenes stimulate cell growth. 1. Genes controlling the cell cycle For example: cyclic dependent kinases 2. Genes controlling DNA repair Colon cancer For example: HNPCC: colon cancer and DNA repair mutations Breast cancer susceptibility genes (BRCA1 and BRCA2) & DNA repair Breast Cancer Tumors 3.Genes affecting chromosome segregation metaphase apc gene and p53 gene required for proper chromosomal separation 4. GENES that promote vascularization Van Hippel-Landau disease ▪ Extensive vascularization ▪ Dominant mutation 5. Telomerase may with cancer Genes that regulate telomerase 6. Genomic Instability Hypomethylation (?) Hypermethylation Gene repression Let’s summarize some key points These Cancer Causing Genes may affect The cell cycle DNA repair Chromosome segregation Changes in chromosome number Telomerase regulation Vascularization Genomic Instability DNA hypomethylation (?) The relationship of p53 and Rb to the cell cycle Cyclins are the control proteins that keep the cell cycle moving. But how?? Cell cycle & cyclins I get it! (and late G1) Another look at the cell cycle Requires E2F (and late G1) But you said p53 is also involved in the cell cycle. Where is it in the picture?! Wt Rb protein are changed by cyclins. Release of Rb mutations prevent E2F binding Under normal (wt) conditions P53 and Rb communicate p21 inhibits phosphorylation step by Preventing cyclin/Cdk complex 1 2 3 4 Cancer : Multi-step process Normal Many mutations Multiple mutations Gain of function Loss of function