world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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GEOGRAPHIC VARIATION IN<br />
MUTATION PATTERNS<br />
Mutations in <strong>cancer</strong> genes are the direct<br />
consequence of attack on DNA by exogenous<br />
or endogenous agents or of errors in<br />
DNA repair systems. By analysing the<br />
type and the sequence context of such<br />
mutations, it is possible to form hypotheses<br />
regarding the nature of the mutagenic<br />
mechanism involved. The most interesting<br />
genes in this respect are those altered<br />
by missense point mutations, such as<br />
members of the RAS family, CDKN2A/<br />
INK4A, and, in particular, the p53 gene.<br />
The p53 gene is the most frequently<br />
mutated gene in human <strong>cancer</strong>, with over<br />
16,000 mutations <strong>report</strong>ed and compiled<br />
in a database maintained at IARC<br />
(http://www.<strong>iarc</strong>.fr/p53). The diversity of<br />
these mutations allows the identification<br />
of patterns which vary depending on the<br />
tumour type, the geographic origin and<br />
the risk factors involved. These are often<br />
specific for particular agents that have<br />
caused these mutations. Thus p53 gene<br />
mutations in <strong>cancer</strong>s may be seen as “fingerprints”<br />
left by carcinogens in the<br />
human genome, which may help to identify<br />
the particular carcinogen involved.<br />
A typical example of such a “fingerprint”<br />
is the mutation at codon 249 observed in<br />
liver <strong>cancer</strong>s of patients from sub-<br />
Saharan Africa and Eastern Asia. In these<br />
regions, liver <strong>cancer</strong> is a consequence of<br />
chronic infection by hepatitis viruses and<br />
of dietary poisoning with aflatoxins, a<br />
Lesions in the p16 INK4A-cyclin D, CDK4-pRb<br />
and p14 ARF-Mdm2-p53 pathways occur so<br />
frequently in <strong>cancer</strong>, regardless of patient<br />
age or tumour type, that they appear to be<br />
fundamental to malignancy [24].<br />
Prospects for the molecular analysis of<br />
<strong>cancer</strong><br />
More than 200 genes that are altered at<br />
variable proportions in different human<br />
102 Mechanisms of tumour development<br />
Fig. 3.24 Geographic variations in the prevalence of p53 gene mutations in breast <strong>cancer</strong>s.<br />
class of mycotoxins which contaminates<br />
traditional diets (groundnuts) (Food contaminants,<br />
p43). Experiments in animals<br />
and in cell culture have shown that aflatoxins<br />
can directly induce the mutation at<br />
codon 249. This particular mutation is not<br />
found in liver <strong>cancer</strong>s in areas of the <strong>world</strong>,<br />
such as the USA, where exposure to aflatoxins<br />
is low.<br />
Specific mutations have also been<br />
observed in lung <strong>cancer</strong>s from smokers<br />
(due to tobacco carcinogens). In skin <strong>cancer</strong>s,<br />
the mutations bear typical chemical<br />
signatures of the damage inflicted to DNA<br />
by exposure to solar ultraviolet radiation. In<br />
other instances, exemplified by patterns of<br />
mutation in breast <strong>cancer</strong>, marked differ-<br />
<strong>cancer</strong> types have been characterized.<br />
Most of these have a powerful impact<br />
on tumour growth. However, it is very<br />
likely that many critical genes with less<br />
penetrant phenotypes remain to be<br />
identified. In particular, the genes<br />
involved in stress reponses, in the control<br />
of oxygen metabolism and in the<br />
detoxification of xenobiotics are all candidates<br />
for a role as cofactors in the<br />
ences have been observed between geographical<br />
areas, which may provide information<br />
on the nature of risk factors<br />
involved.<br />
In many other <strong>cancer</strong>s, mutation patterns<br />
also vary from one region of the <strong>world</strong> to<br />
another. This variability may give clues<br />
about the genetic heterogeneity of populations,<br />
as well as about the diversity of<br />
agents involved in causing <strong>cancer</strong>s. For<br />
example, in oesophageal <strong>cancer</strong>s, mutation<br />
types widely differ between high-incidence<br />
and low-incidence regions, suggesting<br />
that specific mutagens are at<br />
work in causing the excess incidence<br />
seen in some parts of the <strong>world</strong>, such as<br />
Northern Iran and Central China.<br />
<strong>cancer</strong> process. Moreover, many biological<br />
alterations leading to <strong>cancer</strong> may<br />
not be detectable at the DNA level.<br />
Cancer-causing changes may result<br />
from modification of RNA levels or processing,<br />
and of protein structure and<br />
function through a variety of epigenetic<br />
phenomena. The systematic profiling of<br />
gene expression in <strong>cancer</strong> cells will<br />
probably reveal a whole new set of