world cancer report - iarc

GENETIC SUSCEPTIBILITY
SUMMARY
> Inherited cancer syndromes, usually
involving germline mutations in tumour
suppressor or DNA repair genes, may
account for up to 4% of all cancers.
> Inherited mutations of the BRCA1 gene
account for a small proportion of all
breast cancers, but affected family
members have a greater than 70% lifetime
risk of developing breast or ovarian
cancer.
> Identification of a germline mutation
allows for preventive measures, clinical
management and counselling.
> Environmental factors may modify the
cancer risk of individuals affected by
inherited cancer syndromes.
> Altered cancer susceptibility may be
mediated by genetic variations in genes
which, while not causing cancer, affect
metabolism of carcinogens such as
tobacco smoke.
The genetic basis of cancer may be
understood at two levels. Firstly, malignant
cells differ from normal cells as a
consequence of the altered structure
and/or expression of oncogenes and
tumour suppressor genes, which are
found in all cancers. In this case, “the
genetic basis of cancer” refers to
acquired genetic differences (somatic)
between normal and malignant cells due
to mutation in the one individual.
Secondly, the same phrase, “the genetic
basis of cancer” may be used to refer to
an increased risk of cancer that may be
inherited from generation to generation.
This section is concerned with the latter
phenomenon. In many instances, the
genes concerned have been identified,
and have also sometimes been found to
play a role in sporadic cancers as well.
1
mut
1
Marker A
1
mut
Marker B
1
INHERITED
1
wt
1
2
wt
2
2
wt
2
2
wt
2
2
mut
Fig. 2.65 Knudson’s hypothesis, explaining the development of an inherited cancer caused by the inactivation
of a suppressor gene. Tumours of the eye (retinoblastoma) in individuals who have inherited a
mutation in one allele of the retinoblastoma gene on chromosome 13 (“mut” rather than the normal wildtype
“wt”), almost always occur in both eyes, due to inherited susceptibility. When this tumour type
occurs spontaneously in a single retinal cell (“sporadic”) by a somatic mutation, only one eye is affected.
The mechanisms by which the tumour arises can be determined by analysing the genotypes produced
from normal (“N”) and tumour (“T”) tissues.
Interplay between genes and environmental
factors
The influence of lifestyle factors (especially
smoking), occupational exposures,
dietary habits and environmental exposures
(such as air pollution, sun exposure
or low levels of radiation) on the development
of cancer is clear; such factors
account for a specific fraction of cancers.
Another large fraction of cancers is caused
by viral and other infectious agents, this
being particularly relevant to the developing
world. Carcinogenic agents, as diverse
as chemicals, radiation and viruses, act
primarily by damaging DNA in individual
cells. Such damage has broad ramifications
when it involves disruption of genes
which control cell proliferation, repair of
further DNA damage, and ability of cells to
infiltrate (invade) surrounding tissue
2
wt
2
Germline mutation
2
Somatic mutation
wt
PREDISPOSED CELL
1
1
2
wt
2
Loss
1 1
Loss/duplication
mut mut
Recombination
Localized
TUMOUR
AUTORADIOGRAM
N T N T
1
1
1
1
1
(Chapter 3). Because each of these
changes is relatively rare, the chance that
the necessary combination of such events
occurs to allow a normal cell to progress
into a fully malignant tumour is small.
However, the risk to an individual over his
or her lifetime can be as large as 10% for
cancers of the breast or prostate (that is,
in some instances, 10% of the population
will suffer from one of these cancer types
in their lifetime). Genetic alterations accumulate
gradually either through random
events and/or by the action of specific
environmental carcinogens, and thus most
cancers in the population occur in middleaged
and elderly individuals. Some individual
cancers can be attributed to particular
environmental factors. In the absence of
apparent causative factors, a cancer is
described as “sporadic” or “spontaneous”.
1
mut
1
1
2
mut mut
1
2
mut mut
2
N
N
N
A B
T N T
A B
T N T
A B
T N T
A B
Genetic susceptibility 71