Upload
frank-randall
View
221
Download
1
Tags:
Embed Size (px)
Citation preview
Cancer as a genetic
chapter 23 select topics andlecture 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
A photo of a sweat glandHidradenoma: fluid filled benight
Some benign tumors may be enlargements without abnormal
growtheg. CF
Most cancers fall into one of these groups
Carcinomas
Sarcomas
Leukemias
Lymphomas
2009 Estimated US Cancer Deaths*
ONS=Other nervous system.Source: American Cancer Society, 2009.
Men292,540
Women269,800
26% Lung & bronchus
15% Breast
9% Colon & rectum
6% Pancreas
5% Ovary
4% Non-Hodgkin lymphoma
3% Leukemia
3% Uterine corpus
2% Liver & intrahepaticbile duct
2% Brain/ONS
25% All other sites
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%
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
bilateral retinoblastoma autosomal dominant
Li-Fraumeni Syndrome autosomal dominant
osteoclasts neutrophils
P53 and the bax gene
Example
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
Proto-oncogenes Oncogenevirus
mutated in virusControl by viral promoter mutated by virusIn host cell DNA
Possible outcomes of recombination
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
apc gene and p53 gene required for proper chromosomal separation
metaphase
Van Hippel-Landau disease
▪ Extensive vascularization
▪ Dominant mutation
4. GENES that promote vascularization
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??
(and late G1)
Cell cycle & cyclins
I get it!
(and late G1)
Requires E2F
Another look at the cell cycle
But you said p53 is also involved in
the cell cycle. Where is it in the
picture?!
Release of
Wt Rb protein are changed by cyclins.
Rb mutations prevent E2F binding
Under normal (wt) conditions P53 and Rb communicate
1 2 3
p21 inhibits phosphorylation step byPreventing cyclin/Cdk complex
4
Cancer : Multi-step process
No
rmal
Loss of functionGain of function
Can
cerMany mutationsMultiple mutations