world cancer report - iarc

Common human oncogenes
Many common proto-oncogenes encode
components of the molecular cascades
that regulate the cellular response to
mitogenic signals [6]. They include growth
factors (e.g. TGFA), growth factor receptors
(e.g. the receptors for epidermal
growth factor, EGF and its close homologue,
ERBB2), receptor-coupled signal
transduction molecules (in particular, several
small guanosine triphosphate (GTP)binding
proteins located on the inner face
of the cell membrane, such as the various
members of the RAS family), kinases
(SRC, ABL, RAF1), regulatory subunits of
cell cycle kinases (CCND1 and CCNA),
phosphatases (CDC25B), anti-apoptotic
molecules (BCL2) and transcription factors
(MYC, MYB, FOS, JUN). The cumbersome
nomenclature of these genes (Box:
Naming genes and proteins, p101) owes
much to the way they were discovered and
identified. The SRC gene, for example, was
the first oncogene identified, in 1976, as a
modified version of a cellular gene incorporated
in the genome of a highly transformant
chicken retrovirus, the Rous sarcoma
virus. The MYC gene was also originally
identified in the genome of an avian
retrovirus inducing promyelocytic
leukaemia. The RAS genes were first identified
as activated genes capable of inducing
the formation of rat sarcomas, and
various members of the family were found
in different murine retroviruses, such as
the Harvey sarcoma virus (HRAS) and the
Kirsten sarcoma virus (KRAS).
The most commonly activated oncogenes
in human cancers are ERBB2 (in breast
and ovarian cancers), members of the RAS
family (in particular KRAS in lung, colorectal
and pancreatic cancers, and MYC (in a
large variety of tumours such as cancers of
the breast and oesophagus and in some
forms of acute and chronic leukaemia).
These three examples give an excellent
illustration of the diversity of the mechanisms
of oncogene activation and of their
consequences for cell growth and division.
ERBB2
In the case of ERBB2, oncogenic activation
is almost always the result of amplification
of the normal gene [7] (Fig. 3.16). This
A
Fig. 3.16 Analysis of the status of the ERBB2 oncogene by fluorescent in situ hybridization (FISH) with a
rhodamine-labelled ERBB2 probe (pink). In breast tumour cells without amplification of the gene, each
nucleus possesses two copies of ERBB2 (A). In tumour cells with high-level amplification of the gene,
numerous signals are evident in each nucleus (B).
gene is located within a region of the
genome which is amplified in about 27% of
advanced breast cancers, leading to a
spectacular increase in the density of the
molecule at the cell surface. ERBB2
encodes a transmembrane protein with
the structure of a cell-surface receptor, the
intracellular portion of which carries a
tyrosine kinase activity. Overexpression of
ERBB2 leads to constitutive activation of
the growth-promoting tyrosine phosphorylation
signal. The elucidation of this mechanism
has led to the development of neutralizing
antibodies and specific chemical
inhibitors of tyrosine kinase activity as
therapeutic approaches to the blocking of
ERBB2 action.
RAS
The RAS genes are located one step downstream
of ERBB2 in growth signalling cascades.
The protein products of the RAS
genes are small proteins anchored at the
cytoplasmic side of the plasma membrane
by a lipidic moiety. They indirectly interact
A
with activated tyrosine kinases and act as
“amplifiers” to increase the strength of the
signal generated by the activation of cellsurface
receptors [8]. In their active form,
ras proteins bind guanosine triphosphate
(GTP) and catalyse its hydrolysis into
guanosine diphosphate (GDP) returning to
their inactive form. Oncogenic forms of
activated RAS genes often carry missense
mutations at a limited number of codons
within the GTP-binding site of the enzyme,
making it unable to hydrolyse GTP and thus
trapping it in the active form. Activation of
RAS genes thus induces the cell to behave
as if the upstream, Ras-coupled receptors
were being constantly stimulated.
MYC
The MYC oncogene may be seen as a prototype
of the family of molecules which lies
at the receiving end of the signal transduction
cascades. MYC encodes a transcription
factor which is rapidly activated after
growth stimulation and which is required
for the cell to enter into cycle [9].
Fig. 3.17 In cell cultures, activation of a single oncogene may result in a changed morphology from
“normal” (A) to “transformed” (B) and this often corresponds to a change in growth properties. Malignant
transformation appears to require the co-operation of at least three genes.
B
B
Oncogenes and tumour suppressor genes 97