world cancer report - iarc

ONCOGENES AND TUMOUR SUPPRESSOR GENES
SUMMARY
> Human cells become malignant through
the activation of oncogenes and
inactivation of tumour suppressor
genes. The pattern of genes involved
varies markedly at different organ sites.
> Oncogenes stimulate cell proliferation
and may be overexpressed by gene
amplification (e.g. MYC). In addition,
oncogenes may be activated by mutations
(e.g. the RAS gene family).
> Tumour suppressor genes are typically
inactivated by gene mutations in one
allele (gene copy), followed by loss of
the intact allele during cell replication
(two-hit mechanism). This leads to loss
of expression and abolition of the suppressor
function, which is particularly
important in cell cycle control.
> Mutational inactivation of suppressor
genes in germ cells is the underlying
cause of most inherited tumour
syndromes. The same type of mutation
may arise through mutations occurring
during an individual’s lifetime.
Definitions
The multi-step nature of carcinogenesis
has long been recognized (Multistage carcinogenesis,
p84). Over the past 20 years,
experimental studies in animals and
molecular pathological studies have converged
to establish the notion that each
step in malignant transformation is determined
by a limited number of alterations
in a small subset of the several thousands
of cellular genes [1]. The terms “oncogene”
and “tumour suppressor gene” are
commonly used to identify the sets of
genes involved in such sequences of
events [2]. Both groups of genes are
extremely diverse in terms of nature and
function. An oncogene is a gene whose
function is activated in cancer. This can be
achieved by a number of simple molecular
96 Mechanisms of tumour development
mechanisms, including point mutations
that constitutively activate an enzyme,
deletions that remove negative regulatory
regions from proteins, or increased
expression resulting from promoter deregulation
or from multiplication of the number
of copies of the gene (a phenomenon
called “amplification” [3]). Activation of an
oncogene is a dominant mechanism, since
alteration of a single allele is sufficient to
confer a gain of function for cancer onset
or progression. The non-activated counterpart
of an oncogene is sometimes
called a “proto-oncogene”. A proto-oncogene
is in fact a “normal” gene in all
respects, often with important functions
in the control of the signalling of cell proliferation,
differentiation, motility or survival.
A tumour suppressor gene is a gene
whose alteration during carcinogenesis
results in the loss of a functional property
essential for the maintenance of normal
cell proliferation. Loss of function of a
tumour suppressor gene is typically a
recessive mechanism. Indeed, in many
instances both copies of the gene need to
be inactivated in order to switch off the
corresponding function. Inactivation of
tumour suppressor genes proceeds by
loss of alleles (most often through the loss
of entire chromosomal sections encompassing
several dozen genes), small deletions
or insertions that scramble the reading
frame of the gene, transcriptional
silencing by alteration of the promoter
region, or point mutations that change the
nature of residues that are crucial for the
activity of the corresponding protein.
Recently, it has emerged that tumour suppressor
genes can be conveniently subclassified
into two major groups. The
genes of the first group are nicknamed
“gatekeepers”. Their products control the
gates on the pathways of cell proliferation.
Typically, gatekeeper genes are negative
regulators of the cell cycle, acting as
“brakes” to control cell division. The genes
of the second group are called “caretakers”,
as their primary function is not to
control the speed or timing of cell division
but rather its accuracy. Caretaker genes
are usually involved in DNA repair and in
the control of genomic stability. Their
inactivation does not enhance cell proliferation
per se but primes the cell for rapid
acquisition of further genetic changes [4].
The combined activation of oncogenes
and inactivation of tumour suppressor
genes drive the progression of cancer. The
most evident biological consequences of
these alterations are autonomous cell proliferation,
increased ability to acquire
genetic alterations due to deregulated
DNA repair, ability to grow in adverse conditions
due to decreased apoptosis,
(Apoptosis, p113) capacity to invade tissues
locally and to form distant metastases,
and ability to activate the formation
of new blood vessels (a process called
angiogenesis). Together, these five biological
phenomena may be caricatured as
pieces of the “cancer jigsaw” [5] (Fig.
3.15). None alone is sufficient in itself, but
cancer arises when they interact together
into a chain of coordinated events that
profoundly modifies the normal cellular
pattern of growth and development.
Genetic
instability
Angiogenesis
Autonomous
growth
Invasiveness
Unlimited
replicative potential
Fig. 3.15 The cancer jigsaw: multiple functions
must be altered for tumorigenesis to occur.