world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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Peutz-Jeghers polyp<br />
other words, not every tumour will necessarily<br />
exhibit all the genetic changes<br />
established for the tumour type in question.<br />
Moreover, there is often marked<br />
heterogeneity within an individual<br />
tumour: adjacent cells differ. Mapping<br />
and identification of genes involved in<br />
malignant transformation has been a<br />
major component of the study of the<br />
molecular mechanisms of carcinogenesis.<br />
Multiple genetic changes required<br />
The emergence of a malignant cell population<br />
is understood to be the cumulative<br />
effect of multiple (perhaps five, ten or<br />
more) genetic changes, such changes<br />
being accumulated in the course of the<br />
evolution of the cell from normal to malignant.<br />
The genes designated as oncogenes<br />
and tumour suppressor genes (Oncogenes<br />
Dysplasia in hamartoma<br />
Normal Early adenoma Intermediate adenoma Late adenoma<br />
Fig. 3.3 Histological representation of the pathogenesis of colorectal <strong>cancer</strong>. Phenotypic changes in the morphology of the colonic mucosa reflect the sequential<br />
acquisition of genetic alterations.<br />
86 Mechanisms of tumour development<br />
Juvenile polyp<br />
Flat dysplasia<br />
MHAP/Serrated adenoma<br />
Flat adenoma<br />
and tumour suppressor genes, p96) have<br />
been identified in terms of their biological<br />
function [9]. Such genes are among those<br />
that facilitate transmission of growth control<br />
signals from the cell membrane to the<br />
nucleus (that is, signal transduction), that<br />
mediate cell division, differentiation or cell<br />
death and, perhaps most critical of all,<br />
that maintain the integrity of genetic information<br />
by DNA repair and similar processes<br />
(Carcinogen activation and DNA repair,<br />
p89). Since mutations are normally infrequent<br />
events, it seems unlikely that in the<br />
course of a human lifetime a cell would<br />
acquire all the mutations necessary for<br />
<strong>cancer</strong> to develop, unless at some point<br />
the developing cell lost its ability to protect<br />
itself against mutation and gained<br />
what is called a “mutator” phenotype [10].<br />
Thus, alterations in gene structure and<br />
expression which bring about carcinogen-<br />
Loss of mismatch repair<br />
Ulcerative colitis-associated<br />
colorectal carcinoma<br />
Cancer in mixed hyperplastic adenomatous<br />
polyps (MHAP)<br />
Flat <strong>cancer</strong><br />
Cancer<br />
RER + <strong>cancer</strong><br />
(Replication<br />
Error Positive)<br />
esis are being progressively identified<br />
[11]. As noted earlier, members of some<br />
<strong>cancer</strong>-susceptible families inherit mutations<br />
in particular genes that contribute to<br />
<strong>cancer</strong> development, and hence to their<br />
individual risk of disease. However, with<br />
most <strong>cancer</strong>s, the genetic change critical<br />
to carcinogenesis results from damage to<br />
DNA by chemicals, radiation and viruses<br />
(Fig. 3.1). This damage is not entirely and<br />
perhaps not predominantly produced by<br />
exogenous agents but by natural processes,<br />
such as the production of reactive oxygen<br />
species or the spontaneous deamination<br />
of the 5-methylcytosine naturally<br />
present in DNA [13]. Furthermore, as<br />
shown as the second step in Fig. 3.2, biological<br />
change that is heritable may result<br />
from non-genetic processes including the<br />
modulation of gene expression by hypermethylation<br />
[12].