cancer as a genetic chapter 21 pp 627-637 & lecture notes
TRANSCRIPT
Cancer as a genetic
chapter 21pp 627-637 &lecture notes
Cancer is abnormal cell growth.
TUMORS
TUMORS
Malignant Benign
Most cancers fall into one of these groups
Carcinomas
Sarcomas
Leukemias
Lymphomas
Scientists have also defined characteristics of a cancer cell.
Normal Fibroblasts Transformed Fibroblasts
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
Mutations cause loss of function
Normally requires 2 “hits”
Haploinsufficiency
1.
Loss of Heterozygosity
Examples of tumor suppressors
Retinoblastoma gene (rb)
p53 gene
Retinoblastoma: Retinal tumor
Alfred Knudson: 2 hit model of cancer
Breast cancer and p53
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 (?)
Cancer : Multi-step process
No
rmal
Loss of functionGain of function
Can
cerMany mutationsMultiple mutations
Cancer : Multi-step process
Initiation
Clonal expansion
Progression
Expansion
Now, Let’s look more closely at 2 cancers & their multi-step progression
Colon Cancer Retinoblastoma
The relationship of p53 and Rb to the cell cycle
Brief overview: The cell cycle
Mitosis
prophase metaphase
anaphase telophase
Interphase
Cyclins are the control proteins that keep the cell cycle moving.
But how??
(and late G1)
Cell cycle & cyclins
I get it!
Release of
Wt Rb protein are changed by cyclins.
Rb mutations prevent E2F binding
(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?!
Under normal (wt) conditions P53 and Rb communicate
1 2 3
p21 inhibits phosphorylation step byPreventing cyclin/Cdk complex
4