world cancer report - iarc

Parent
heterozygous
for RB1
Chromosome 13
with deletion
of RB1
Redox changes
Temperature?
Normal
chromosome 13
RB1
Proliferation
Proliferating retinoblastoma cells
X-rays
γ-rays
Hypoxia
Child
heterozygous
for RB1
Somatic mutation with high frequency
in retinal cell with loss of
normal chromosome
UV
Binding to p53-interacting proteins
Normal
Parent
Nonmalignant
cells
Fig. 3.18 The retinoblastoma gene is a paradigm
for tumour suppressor genes: if a child inherits a
mutation or deletion of one copy (“allele”) of the
retinoblastoma gene, the remaining normal copy
tends to be lost at a high frequency in cells of the
retina, resulting in loss of function and in the formation
of tumours. The diagram shows loss of the
whole normal chromosome but the normal allele
can also be lost by mutation, deletion, gene conversion
or mitotic recombination.
Fig. 3.19 Many types of biological stress lead to a p53-mediated response.
98 Mechanisms of tumour development
Cytotoxic
drugs
Activation or accumulation of p53 protein
Myc transactivates a number of other cellular
genes and has a wide spectrum of
molecular effects (a phenomenon that
may explain why Myc is activated in many
different types of cancer cells).
Activation of Myc often proceeds through
amplification of the region containing the
gene on chromosome 8, but Myc is also
commonly activated by chromosomal
translocation in some forms of B-cell
leukaemia (Leukaemia, p242).
BCL2
The BCL2 gene (activated in B cell lymphomas)
exemplifies another kind of
oncogene. Initially identified as a gene
located within a chromosomal breakpoint
in some forms of leukaemia, BCL2 was
found to encode a protein capable of
extending the life span of a cell by preventing
the onset of programmed cell
death, or apoptosis [10] (Apoptosis,
p113). Biochemical studies have revealed
that BCL2 encodes a regulator of the permeability
of the mitochondrial membrane.
Mitochondrial damage and cytoplasmic
leakage of mitochondrial components
is one of the important signals that
lead a cell to apoptosis. By helping to
keep the mitochondrial permeability
pores closed, Bcl-2 protein prevents this
leakage and thus allows the survival of
cells that would otherwise have been
eliminated by a physiological process.
Cytokines
Ribonucleotide
depletion
Microtubule
depletion
Growth factor
depletion
Induction of p53 target genes
Senescence
Tumour suppressor genes: history of a
concept
Whereas the study of retroviruses and
gene transfection experiments were the
keys to the discovery of oncogenes,
tumour suppressor genes were identified
through the study of large DNA viruses
and the analysis of familial tumour syndromes.
Retinoblastoma
In 1971, Knudsen proposed the now popular
“two hits” hypothesis to explain the
inheritance of retinoblastoma, a rare
childhood tumour type [11,12] (Genetic
susceptibility, p71). He postulated that, in
a familial setting, individuals may inherit
only one normal copy of the gene (localized
by linkage studies to chromosome
13q14), the other being either lost, partially
deleted or otherwise inactivated.
Consequently, these individuals would just
need one additional mutagenic step to
switch off the remaining copy of the gene,
thus totally losing the corresponding function
(Fig. 3.18). The very same type of cancer
may also occur in a sporadic manner,
but in this case it would require two consecutive
“hits” (mutagenic events) to inactivate
the two copies of the gene in the
same cell. This theory paved the way for
the modern concept of recessive tumour
suppressor genes. In 1988, the gene
responsible for familial retinoblastoma
was identified [13]. The RB1 gene encodes
a protein that binds and inactivates transcription
factors that are essential for the
progression of the cell cycle, thus fulfilling
the functions of a molecular “brake” on
cell division.
Large DNA viruses
In parallel with events previously outlined,
it became evident that many DNA viruses
associated with cancer encode complex
viral proteins that are capable of sequestering
and inactivating cellular proteins
[14]. This is the case of a tumorigenic
simian virus, SV40, of several adenoma
and polyoma viruses and of oncogenic
forms of human papillomaviruses. In the
case of SV40, the virus encodes a large
protein (called LT for Large Tumour antigen)
which binds two cellular proteins, the