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