Cancer as a genetic chapter 21 pp 627-637 & lecture notes

How cancer genes do alter a cell’s phenotype? 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. TUMORS

TUMORS Malignant Benign

Most cancers fall into one of these groups Carcinomas Sarcomas Leukemias Lymphomas

2009 Estimated US Cancer Deaths* Men 292,540 Women 269,800 Lung & bronchus 30% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4% bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis 3% All other sites 25% 26% Lung & bronchus 15% Breast 9% Colon & rectum 6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 3% Leukemia 3% Uterine corpus 2% Liver & intrahepatic bile duct 2% Brain/ONS 25% All other sites Lung cancer is, by far, the most common fatal cancer in men (30%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death. ONS=Other nervous system. Source: American Cancer Society, 2009.

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 P53 gene and breast cancer

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

Oncogene Possible outcomes of recombination Proto-oncogenes virus Control by viral promoter 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 (?)

Cancer : Multi-step process Normal Many mutations Multiple mutations Gain of function Loss of function

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)

Rb mutations prevent E2F binding Wt Rb protein are changed by cyclins. Release of Rb mutations prevent E2F binding

Another look at the cell cycle Requires E2F (and late G1)

But you said p53 is also involved in the cell cycle But you said p53 is also involved in the cell cycle. Where is it in the picture?!

1 4 2 3 Under normal (wt) conditions P53 and Rb communicate p21 inhibits phosphorylation step by Preventing cyclin/Cdk complex 1 4 2 3