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