1. Genetics of Cancer

3. Genetics of Cancer
Cancer is caused by accumulations of mutations that cause cells to divide inappropriately

4. Genetics of Cancer
Cancer results from genetic changes that affect cell cycle control

5. Oncogenes and Proto-Oncogenes
Are normal cellular genes that code for proteins that stimulate normal cell growth and division
Oncogenes
Are cancer-causing genes
cells have hyperactive growth and division, immortality

6. Mutations make proto-oncogenes excessively active
Converts them to oncogenes, which may promote excessive cell division and cancer
Proto-oncogene
DNA
Translocation or transposition:
gene moved to new locus,
under new controls
Gene amplification:
multiple copies of the gene
Point mutation
within a control
element
within the gene
Oncogene
Normal growth-stimulating
protein in excess
Hyperactive or
degradation-
resistant protein
New
promoter
Figure 19.11

7. The ras gene is a proto-oncogene
When mutated, it produces the Ras protein in excess, which causes the cell to grow and divide without the proper signals
1 Growth
factor
Figure 19.12a
(a) Cell cycle–stimulating pathway.
This pathway is triggered by a growth
factor that binds to its receptor in the
plasma membrane. The signal is relayed to
a G protein called Ras. Like all G proteins, Ras
is active when GTP is bound to it. Ras passes
the signal to a series of protein kinases.
The last kinase activates a transcription
activator that turns on one or more genes
for proteins that stimulate the cell cycle. If a
mutation makes Ras or any other pathway
component abnormally active, excessive cell
division and cancer may result. 1 2 4 3 5
GTP
Ras
Hyperactive
Ras protein
(product of
oncogene)
issues signals
on its own
NUCLEUS
Gene expression
Protein that
stimulates
the cell cycle P
MUTATION
DNA
G protein 3
Protein kinases
(phosphorylation
cascade) 4 2
Receptor
Transcription
factor (activator) 5

8. Tumor-Suppressor Genes
Encode proteins that inhibit abnormal cell division
When inactive, cells cannot control the cell cycle or accurately replicate DNA

9. (b) Cell cycle–inhibiting pathway. In this
The p53 gene encodes a tumor-suppressor protein
That is a specific transcription factor that promotes the synthesis of cell cycle–inhibiting proteins UV
light
DNA
Defective or
missing
transcription
factor, such as
p53, cannot
activate
MUTATION
Protein that
inhibits
the cell cycle
pathway, DNA damage is an intracellular
signal that is passed via protein kinases
and leads to activation of p53. Activated
p53 promotes transcription of the gene for a
protein that inhibits the cell cycle. The
resulting suppression of cell division ensures
that the damaged DNA is not replicated.
Mutations causing deficiencies in any
pathway component can contribute to the
development of cancer.
(b) Cell cycle–inhibiting pathway. In this 1 3 2
Protein kinases 2 3
Active
form
of p53
DNA damage
in genome 1
Figure 19.12b

10. Mutations that knock out the p53 gene
Can lead to excessive cell growth and cancer
(c)
Effects of mutations. Increased cell division, possibly leading to cancer, can result if the cell cycle is overstimulated, as in (a), or not inhibited when it normally would be, as in (b).
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
Cell cycle
overstimulated
Increased cell
division
Cell cycle not
inhibited
Figure 19.12c

11. Results of Oncogene and Tumor Suppressor Mutations
Many oncogenes and tumor suppressor genes
Cause cells to divide when they should not
They are mutated
They are already surrounded by cells

12. Cancer cells lose contact inhibition
Allows them to form tumors

13. The Multistep Model of Cancer Development
Normal cells are converted to cancer cells
By the accumulation of multiple mutations affecting proto-oncogenes and tumor-suppressor genes

14. A multistep model for the development of colorectal cancer
Colon
Colon wall
Normal colon
epithelial cells
Small benign
growth (polyp)
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)
1 Loss of tumor-
suppressor
gene APC (or
other)
4 Loss of
tumor-suppressor
gene p53
2 Activation of
ras oncogene
3 Loss of
tumor-
suppressor
gene DCC
5 Additional
mutations
Figure 19.13

15. When cells “metastasize” they will spread throughout the body, becoming more difficult to treat

16. Certain viruses
Promote cancer by integration of viral DNA into a cell’s genome

17. Inherited Predisposition to Cancer
Individuals who inherit a mutant oncogene or tumor-suppressor allele
Have an increased risk of developing certain types of cancer