world cancer report - iarc

The stages in tumorigenesis have been
designated “initiation”, which encompasses
damage to, and then division of
exposed cells such that their growth
potential is changed irreversibly, and
“progression”, denoting multiple rounds
of cell replication mediating the gradual
transition of an initiated cell towards
autonomous, cancerous, growth. Ultimate
spread of malignant cells resulting in multiple
tumour sites has been termed
“metastasis”. The unequivocal identification
by the mid-1970s of these various
phases was one indication that carcinogenesis
is a multistage process. Arguably,
the greatest achievement of cancer
research during the last decades of the
20th century has been the elucidation of
multistage carcinogenesis at the molecular
genetic level.
The molecular basis of tumour
pathology
In a seminal publication, Vogelstein and
colleagues [7] provided evidence that
the different stages in the cellular evolution
of colon cancer in humans, histologically
identified as hyperplasia,
early-stage adenoma, late-stage adenoma
etc., could be identified with specific
successive genetic changes (Fig.
3.2). The genetic changes included
oncogene activation by mutation at
specific sites and loss of chromosomal
regions (necessarily involving multiple
genes) which were subsequently shown
to be the location of tumour suppressor
genes. Since that initial description,
knowledge of the molecular genetic
basis for human colon cancer has been
massively extended (Colorectal cancer,
p198). For most tumours, the genetic
changes are not inherited from our parents
but arise in a previously normal
cell. The progeny of this cell after cell
division carry the same genetic change
but the surrounding cells remain normal.
Because these genetic changes
affect only the cancer cells, they are
not passed on to the children of cancer
patients. However, in a minority of
cases some critical changes are inherited,
giving a familial predisposition to
colon or other cancers.
Factor Cancer site/cancer
Hormones Estrogens, progesterone Uterus, mammary gland
Gonadotrophins Ovary, testis, pituitary
Testosterone Prostate gland
Pharmaceutical Oral contraceptives Liver
products Anabolic steroids Liver
Analgesics Renal pelvis
Miscellaneous Bile acids Small intestine
substances Saturated fatty acids Colon
Salt Stomach
Tobacco Oral cavity, lung, bladder etc.
Saccharin, uracil, melamine, Urinary bladder
tetraphthalic acid and other
xenobiotics causing urinary stones
Dichlorobenzene, trimethylpentane Kidney
(lead-free gasoline), perchloroethylene
Butylated hydroxyanisole, propionic Stomach
acid
Nitrilotriacetate Kidney
Table 3.1 Promoting agents: non-genotoxic agents that facilitate carcinogenesis by stimulating cell division.
Tobacco smoke also contains genotoxic carcinogens.
CHROMOSOME: 5q
ALTERATION: Mutation
GENE: FAP
Normal
epithelium
Hyperproliferative
epithelium
DNA
hypomethylation
Early
adenoma
12p
Mutation
KRAS
Fig. 3.2 The original Vogelstein model for the genetic and histological evolution of colon cancer.
(Colorectal cancer, p198).
Commonality and heterogeneity
The molecular biological basis of multistage
carcinogenesis initially described
for colon cancer appears to have application
to all tumour types, although
there is marked variation in the extent
to which genes relevant to particular
tumours have been identified [8]. Some
genes, and the corresponding change
associated with tumorigenesis (mutation,
overexpression, deletion and/or
Intermediate
adenoma
18q
Loss
DCC?
Late
adenoma
17p
Loss
p53
Other
alterations
Carcinoma Metastasis
amplification) are common to a number
of tumour types. However, each tumour
type is associated with a distinctive set
of gene alterations. The genes in question
are discussed under the subheading
Pathology and genetics for each of
the tumour types included in Chapter 5.
Such enumeration of relevant genes
necessitates a degree of simplification.
There is clear heterogeneity between
individual tumours of the same type. In
Multistage carcinogenesis 85