world cancer report - iarc

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