Transcript Cancer as a genetic disease

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