Oncogenes and tumour
suppressor genes 1
Cancer mutations occur in two forms
Oncogenes
Gain-of-function dominant mutations
Tumour suppressor genes
loss of function mutations
Oncogenes
• Genes known as proto-oncogenes code for
proteins that stimulate cell division
• mutated forms, called oncogenes, cause
stimulatory proteins to be overactive, with the
result that cells proliferate excessively
• gain of function mutations
Some acronyms!
•
•
•
•
•
•
Myc
Sis
Erb
Src
Ras
Yes
• Abl
• Fos
• jun
Myelocytomatosis
Simian sarcoma
Erythroblastoma
Rous sarcoma virus
Rat sarcoma
2 viruses Y73 & ESH sarcoma, isolated from
a chicken owned by Mr. Esh
Abelson murine leukaemia virus
Finkel biskis jinkins reilly mouse sarcoma
junana
Two approaches to identifying oncogenes
• Analysis of tumor
causing
retroviruses
• Exposure of
noncancerous cells to
tumor DNA in culture
– Human tumor DNA to
transform normal
mouse cells
– Human DNA isolated
from transformants
Activation of proto-oncogenes
• Viral insertion
• Chromosomal rearrangements
– Altered regulation
– Fusion genes
• Gene amplification
• Point mutations
• Loss of degradation signals
Viral insertion
Chromosomal rearrangements – altered regulation
Burkitts lymphoma
All patients show t(8:14)
translocation of the
immunoglobulin gene on
chromosome 14 to the c-myc
oncogene locus on
chromosome 8
c-myc is under regulatory
control of IgH resulting in
overexpression of the
oncogene
Chromosomal rearrangements - fusion gene
Chronic Myelogenous Leukaemia
Translocation t(9:22)
Abl-bcr fusion gene encodes a constitutively active protein tyrosine
kinase, which affects cell cycle, adhesion and apoptosis
Gene amplification
Metaplastic breast carcinomas (MBCs)
account for less than 1% of all
invasive mammary carcinomas.
Approximately 70–80% of metaplastic
breast carcinomas overexpress the
epidermal growth factor receptor
(EGFR).
Human epidermal growth factor
receptor (HER2) Herceptin©
EGFR gene amplification in MBC (>5
signals per nucleus). Note the bizarre
neoplastic cell with more than
10 copies of EGFR.
point mutations
Point mutations in ras,
implicated in bladder
carcinoma
e.g. GGC to GTC (G12V)
Loss of degradation signals
Epstein–Barr virus (EBV)
associated with lymphoid
and epithelial
malignancies.
Three viral proteins,
EBNA1, LMP-1 and -2A,
constitutively activate cmyc oncogene by
decreasing ubiquitindependent proteolysis of
this protein and
upregulate compensatory
pathways in Burkitt’s
lymphomas.
Seminars in Cancer Biology Volume 13, Issue 1 , February 2003, Pages 69-76
Growth factor signalling and oncogenes
Cell Cycle Control is through the effects
of growth factors which interact with
membrane-bound glycoprotein
receptors that transduce the message
via a series of intracellular signals that
promote or inhibit the expression of
specific genes.
Molecular components of each
signaling system
• Growth factors – hormones and cell-bound signals
that stimulation or inhibit cell proliferation
• Receptors – membrane bound proteins that accept
signals
– signal-binding site
– transmembrane segment
– intracellular domain
Fig. 18.15 a
Signal transducers relay messages and
transcription factors activate expression of
genes
Fig. 18.15 c
Growth factors
Growth factor receptor
Mutations in GF receptor can cause
ligand-independent activation
Figure 5.12a The Biology of Cancer (© Garland Science 2007)
Other growth factor receptors
Figure 5.10 The Biology of Cancer (© Garland Science 2007)
Normal fibroblasts
+/- PDGF
-
+
PDGF receptor
negative fibroblasts
+/- PDGF
-
+
Figure 5.4a The Biology of Cancer (© Garland Science 2007)
c-crk (cell cycle related kinase)
Adaptor proteins
Ras
Small GTP-binding signalling
molecule
Guanine nucleotide exchange factor
(GEF) - activation by GDP to GTP
GTPase activation proteins (GAP)
- inactivation by GDP to GTP
V-ras or mutated ras has lost the
ability to interact with accessory
proteins and are either GEF
independent or GAP insensitive
(GTP state)
Genetics of brain cancer
• Glioblastoma multiforme (GBM)
– Aggressive cancer of glial cells
– Heterogeneous condition resulting from mutation in different
subset of genes
• Glial cells
– Astrocytes – provide support for neurons
– Oligodendrocytes – produce myelin sheaths
– Ependymal cells – line the brain cavities known as ventricles and
regulate cerebrospinal fluid production
• Grades of gliomas
–
–
–
–
Lowgrade (II)
Anaplastic (III)
GBM (IV)
Low grades progress to higher grades
Many genes in various combinations produce GBMs
Three routes for evolution of GBM have been identified
Pathway from grade II astrocytoma
to malignant GBM
Fig. 18.27
Some rapidly arising GBMs have
no apparent precursors
• Oncogenic amplification of the epidermalgrowth-factor-receptor (EGFR) gene and loss of
regions from 10p and 10q
• Arise de novo or so rapidly no precursors are
detectable
• Rarely occur in astrocytoma-derived GBM
tumors with p53 mutations and 17q deletions
• Occur in significantly older adults than GBMs
with mutant p53 and chromosome 17 deletions
Summary of GBM
• GBM phenotypes
– Develop by different combinations of mutations
in different pathways
• Lower-grade astrocytomas via p53 and RB gene
inactivations
• Oligodendroglial tumors via deletions of chromosome
1 and 19
• de novo via EGFR gene activation
– Mutational pathways are often more complicated
• Not every GBM shows all genetic changes described
• Some GBMs derived from one type of cell have
mutations associated with another type of cell
GENES
Further examples of oncogenes
Genes for growth factors or their receptors
PDGF
Codes for platelet-derived growth factor. Involved in glioma (brain cancer)
erb-B
Codes for the receptor for epidermal growth factor. Involved in
glioblastoma (brain cancer) and breast cancer
erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor. Involved in
breast, salivary gland and ovarian cancers
RET
Codes for a growth factor receptor. Involved in thyroid cancer
Genes for cytoplasmic relays in stimulatory signaling pathways
Ki-ras
Involved in lung, ovarian, colon and pancreatic cancers
N-ras
Involved in leukemias
Genes for transcription factors that activate growth promoting genes
c-myc
Involved in leukemias and breast, stomach and lung cancers
N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma
L-myc Involved in lung cancer
Genes for other molecules
Bcl-2
Codes for a protein that normally blocks apoptosis. Involved in follicular B
cell lymphoma
Bcl-1
Also called PRAD1. Codes for cyclin D1, a stimulatory component of the
cell cycle clock. Involved in breast, head and neck cancers
MDM2
Codes for an antagonist of the p53 tumor suppressor protein. Involved
sarcomas (connective tissue cancers) and other cancers
References
Chapter 5: Biology of Cancer by RA Weinberg
AND/OR
Chapter 6: Cancer Biology (2nd edition) by
RJB King:
Optional reading:
Oncogenes by Amanda Perry (www.els.net)