world cancer report - iarc

product of the RB1 gene (pRb) and an
ubiquitous protein that was conservatively
called p53. In the case of oncogenic
human papillomaviruses, the viruses
encode two distinct proteins, E7 (which
neutralizes pRb) and E6 (which neutralizes
p53). Thus it was suggested that pRb and
p53 might have similar, complementary
functions, operating jointly in the control
of cell division.
The “missing link” in this conceptual edifice
was the discovery of alterations in the
gene encoding p53. This was achieved in
1989, when it emerged that the p53 gene
was often mutated and/or deleted in
many forms of cancers [15]. In 1991,
inherited loss of p53 was found to be
associated with a rare familial syndrome
of multiple cancers, the Li-Fraumeni syndrome,
in which afflicted family members
suffer vastly increased incidence of many
tumour types [16]. Today, about 215 families
worldwide affected by this syndrome
have been described and the p53 mutations
they exhibit are compiled in a database
maintained at IARC.
Tumour suppressor genes and familial
cancer syndromes
Most familial cancer syndromes are
inherited as a recessive trait, and correspond
to the constitutive inactivation
of an important tumour suppressor
gene, as described above in the case of
familial retinoblastoma. Over the past
15 years, many loci containing tumour
suppressor genes have been identified
by linkage studies in cancer-prone families.
Colorectal cancer
In colorectal cancers, two different familial
cancer syndromes have been found to
be associated with the constitutive alteration
of two distinct sets of tumour suppressor
genes (Colorectal cancer, p198).
Patients with familial adenomatous polyposis,
a disease that predisposes to the
early occurrence of colon cancer, often
carry alterations in one copy of the adenomatous
polyposis coli (APC) gene [17].
This gene plays a central role in a signalling
cascade that couples cell-surface
receptors, calcium-dependent adhesion
molecules and transcription factors that
regulate cell proliferation. Loss of APC
function sets these transcription factors
free, an event that favours not only the
formation of polyps but also their transformation
into adenomas and carcinomas.
Breast cancer
Two genes have been identified as
involved in familial breast cancer risk,
BRCA1 and BRCA2 [18]. These genes
encode large proteins with complex
functions in many aspects of cell regulation,
such as cell cycle control and
DNA repair. However, how their inactivation
contributes to the onset or
development of breast cancer is still
largely unknown.
A B
Others
In the case of hereditary Wilms tumours, a
rare type of kidney cancer, the gene identified
encodes a protein essential for the correct
differentiation of the nephron. This very
specific role may explain why the hereditary
loss of this gene does not seem to be associated
with cancers at any other site.
This short overview gives only a few examples
of the diversity of tumour suppressor
genes, and there is little doubt that many
still remain to be identified. Given the
breadth of the concept of “tumour suppressors”,
many genes encoding components of
stress response pathways have the potential
to behave in this fashion (as their alteration
may prevent cells from mounting an
adequate response to genotoxic, potentially
Fig. 3.20 Accumulation of p53 in human epidermis after exposure to sunlight. Unexposed skin shows no
immunostaining against p53 protein (A). Exposed skin (B) shows a dense dark nuclear coloration of epidermal
cells due to positive immunostaining for p53 protein.
14 - 3 -3 σ p21 p53R2
RPA
TFIIH
cdc25 Cdk PCNA
G2
G1 G1/S
Cell cycle arrest
Replication/
Transcription/
Repair
Bcl-2
Bax
IGF/BP3
Killer/DR5
PAG608
PIG3
Transcriptional activation
Transcriptional repression
Protein interactions
Apoptosis
Unknown
proteins?
Fig. 3.21 Multiple response pathways are triggered by the accumulation of p53 in the cell nucleus.
Oncogenes and tumour suppressor genes 99