world cancer report - iarc

Fig. 3.22 Molecular modelling of part of the p53 protein (DNA-binding domain), showing its interaction
with DNA. The amino acids labelled (arginine 175, 248, 273) are important for maintaining biological
activity and are among the “hotspots” for mutations in cancer. The zinc atom is required for stabilizing
the complex three-dimensional structure of the p53 oligomer.
Exon 1 β
Fig. 3.23 Generally, a single segment of DNA codes for a single protein. However, the p16 and p14 ARF
proteins are both encoded by a single region of DNA. P = promoter.
oncogenic forms of stress). The genes
responsible for complex inherited diseases
such as ataxia telangiectasia or xeroderma
pigmentosum (Carcinogen activation and
DNA repair, p89) belong to this category
[19]. Alteration of such genes results in
many defects, including hypersensitivity to
radiation and therefore to the development
of cancers such as skin tumours.
Tumour suppressor genes and sporadic
cancers
Many of the tumour suppressor genes
associated with familial cancer syndromes
100 Mechanisms of tumour development
Exon 1 α Exon 2 Exon 3
CDKN2A/
INK4A
gene
p16
Inhibitor of
cyclin D/CDK4
complexes
INK4A
p14
Inhibitor of p53-
Mdm2 complex
formation
ARF
are also mutated at variable rates in many
forms of sporadic cancer. However, two of
them, p53 and CDKN2A, are very commonly
altered in almost every kind of
human cancer.
p53, the guardian of the genome
The p53 gene encodes a phosphoprotein
of molecular weight 53,000 daltons,
which accumulates in the nucleus in
response to various forms of stress, in
particular, DNA damage (Fig. 3.20). In this
context, p53 acts as a transcriptional regulator,
increasing or decreasing the
expression of several dozen genes
involved in cell cycle control, in the induction
of apoptosis, in DNA repair and in differentiation
control. Together these genes
exert complex, anti-proliferative effects
(Fig. 3.21). Essentially, when cells are subjected
to tolerable levels of DNA-damaging
agents, activation of p53 will result in
cell cycle arrest, temporarily removing the
cells from the proliferative pool or mediating
differentiation. However, when faced
with highly damaging levels of genotoxic
stress, p53 will induce apoptosis, a programmed
form of suicide that eliminates
cells with potentially oncogenic alterations.
This complex role in the protection
of the cell from DNA damage has resulted
in p53 being described as the “guardian of
the genome” [20]. Loss of this function by
mutation, as often occurs during carcinogenesis,
will allow cells with damaged
DNA to remain in the proliferative population,
a situation that is essential for the
expansion of a clone of cancer cells.
The p53 gene differs from most other
tumour suppressors in its mode of inactivation
in human cancers. Whereas most
tumour suppressors are altered by loss of
alleles or inactivating deletions or insertions,
p53 is commonly the target of
point mutations within the portion of the
gene that encodes the DNA-binding
domain of the protein (Fig. 3.22). These
mutations prevent the correct folding of
this protein domain, and therefore disrupt
the interactions of p53 with its specific
DNA targets. However, the mutant
proteins are often extremely stable and
therefore accumulate to high levels within
the nucleus of cancer cells. This accumulated
protein can often be detected by
immunohistochemistry in primary tumours
as well as in distant metastases. Although
not all mutations induce accumulation of
the protein, p53 accumulation provides a
convenient tool for pathologists to assess
the possibility of a p53 dysfunction in
cancer specimens [21].
Mutation is not the only way to alter p53
protein in cancer. In cervical cancers,
p53 gene mutations are infrequent, but
the protein is inactivated by binding of
the viral protein E6 which is produced by
human papillomavirus. This protein cre-