cancer as a genetic chapter 23 select topics and lecture notes
TRANSCRIPT
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Cancer as a genetic
chapter 23 select topics andlecture notes
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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
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Cancer is abnormal cell growth.
Lead to
TUMOR is NOT = CANCER
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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
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Most cancers fall into one of these groups
Carcinomas
Sarcomas
Leukemias
Lymphomas
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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%
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Characteristics of Cancer
Loss of contact inhibition
Loss of apoptosis
Growth in soft agar
Tumor growth “in vivo”
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2 broad groups of cancer causing genes
1. Tumor suppressor genes
2. Oncogenes
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1. Tumor Suppressors
Normally requires 2 “hits”
Mutations cause loss of function
haploinsufficiency
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Alfred Knudson: 2 hit model of cancer
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1.
Loss of Heterozygosity
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Examples of tumor suppressors
Retinoblastoma gene (rb)
p53 gene
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Retinoblastoma: Rb gene and Retinal tumor
P53 gene and breast cancer
bilateral retinoblastoma autosomal dominant
Li-Fraumeni Syndrome autosomal dominant
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osteoclasts neutrophils
P53 and the bax gene
Example
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Nobel Prize in 2002 for their discovery of apoptosis
Brenner
Horvitz
Sulston
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2. Oncogenes
■ Second group of cancer causing genes
■ Mutations cause a gain of activity
■ Requires only one “hit”
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2.
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Where do Oncogenes originate?
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Hypothesis of origin of oncogenes
Viruses recombine with proto-oncogenes
Michael Bishop and Harold Varmus
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Proto-oncogenes Oncogenevirus
mutated in virusControl by viral promoter mutated by virusIn host cell DNA
Possible outcomes of recombination
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Here are some examples of how tumor suppressors and oncogenes stimulate cell
growth.
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1. Genes controlling the cell cycle
For example: cyclic dependent kinases
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2. Genes controlling DNA repair
Colon cancer
For example: HNPCC: colon cancer and DNA repair mutations
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Breast cancer susceptibility genes (BRCA1 and BRCA2) & DNA repair
Breast Cancer Tumors
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3.Genes affecting chromosome segregation
apc gene and p53 gene required for proper chromosomal separation
metaphase
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Van Hippel-Landau disease
▪ Extensive vascularization
▪ Dominant mutation
4. GENES that promote vascularization
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5. Telomerase may with cancer
Genes that regulate telomerase
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6. Genomic Instability
Hypomethylation (?)
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Hypermethylation
Gene repression
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Let’s summarize some key points
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These Cancer Causing Genes may affect
The cell cycle
DNA repair
Chromosome segregation Changes in chromosome number
Telomerase regulation
Vascularization
Genomic Instability DNA hypomethylation (?)
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The relationship of p53 and Rb to the cell cycle
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Cyclins are the control proteins that keep the cell cycle moving.
But how??
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(and late G1)
Cell cycle & cyclins
I get it!
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(and late G1)
Requires E2F
Another look at the cell cycle
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But you said p53 is also involved in
the cell cycle. Where is it in the
picture?!
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Release of
Wt Rb protein are changed by cyclins.
Rb mutations prevent E2F binding
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Under normal (wt) conditions P53 and Rb communicate
1 2 3
p21 inhibits phosphorylation step byPreventing cyclin/Cdk complex
4
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Cancer : Multi-step process
No
rmal
Loss of functionGain of function
Can
cerMany mutationsMultiple mutations
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