world cancer report - iarc

Cancer genes
The fact that cancer can “run in families”
has been recognized for over a century.
Among the earliest recorded evidence for
inherited susceptibility is a description by a
Parisian physician, Paul Broca, of a family
with many cases of early onset breast cancer,
liver cancer or other tumours [2]. Such
families have proven to be key resources in
establishing the inheritance of disease
from generation to generation. By analysing
DNA extracted from a blood or tumour
sample from members of these families,
the inheritance of cancer susceptibility
within a family can be tracked to determine
whether the disease is transmitted from
parent to child together with a “genetic
marker”, that is, a gene sequence which
may not have any clinical significance but
which is highly variable between individuals.
If this is the case, and if this is also true
for a sufficient number of other families,
the approximate location of the gene causing
the disease can be determined. From
there, it is a matter of using more molecular-based
strategies to home in on and
identify the specific gene involved and
localize the predisposing gene to a small
region within the overall human genome.
This allows the identification of the specific
genes involved and of the alterations in
those genes predisposing an individual to
cancer [3].
Specific genes involved in susceptibility to
many forms of cancer, both rare tumours
such as retinoblastoma, and more common
cancers such as breast and colon, have
been identified and are designated as
“tumour suppressor genes” or “oncogenes”
(Oncogenes and tumour suppressor
genes, p96). For other forms of inherited
cancer, only the chromosomal location of a
putative susceptibility gene is known; the
specific gene involved has not yet been
identified. Many of the early successes
involved identifying the genetic defects,
and subsequently the genes responsible for
specific cancer-associated syndromes
such as neurofibromatosis, familial adenomatous
polyposis and Li-Fraumeni syndrome.
Neurofibromatosis types are
respectively associated with NF1 and NF2
genes: neurofibromatosis type 1 suffer
from particular skin pigmentation and risk
Gene Location Associated tumours
BRCA1 17q Breast, ovary, colon, prostate
BRCA2 13q Breast, ovary, pancreas, prostate
p16 INK4A 9p Melanoma, pancreas
CDK4 6q Melanoma, other tumours (rarely)
hMLH1 3p Colorectal, endometrial, ovarian cancer
hMSH2 2p Colorectal, endometrial, ovarian cancer
hMSH6 2p Colorectal, endometrial, ovarian cancer
PMS1 2q Colorectal cancer, other tumours (rarely)
PMS2 7p Colorectal cancer, other tumours (rarely)
HPC2 17p Prostate (rarely)
Table 2.21 High-risk susceptibility genes and their chromosomal location. Inherited mutations in these
genes are associated with some common cancers.
of phaeochromocytoma, neurofibroma,
gliomas and other tumours, while type 2
patients develop schwannomas and some
other brain tumours [4]. Individuals afflicted
with adenomatous polyposis, which is
attributable to alterations in the APC gene,
suffer from multiple premalignant lesions in
the colon [5] (Multistage carcinogenesis,
p84). In some, but not all such instances,
the genes in question are also involved in
sporadic cancers. Although the functions of
these genes are not completely characterized,
many appear to be involved either in
key cellular processes such as control of
the cell cycle, programmed cell death, or in
repair and/or detection of DNA damage. In
the rarer inherited cancer syndromes for
which lifetime risks are very high, usually
there are recognizable phenotypic features
which make the syndrome easy to identify
clinically, and a single genetic defect
accounts for the majority of occurrences
(Table 2.20). Other genes are associated
with more common cancers, where there is
a predominant type of cancer without other
distinguishing clinical characteristics (Table
2.21). For some such genes, the actual
genetic defect is not known but convincing
evidence for a chromosomal localization
has been reported. It should be noted that
such distinction between the rarer inherited
cancer syndromes and more common
cancers is sometimes arbitrary.
Prevalence, risks and impact of inherited
cancer
The lifetime risks of cancer due to mutations
in cancer predisposition genes can be
very high; a woman who carries a mutated
BRCA1 gene has a lifetime risk of approximately
70% of developing either breast or
ovarian cancer, compared with women lacking
such mutations [6]. For some of the rare
syndromes, risks of cancer can be even
higher. Nonetheless, mutations in cancer
predisposition genes are relatively unusual,
ranging from 1/100,000 for very rare diseases
such as Cowden syndrome, to
1/10,000 for germline p53 gene mutations
involved in Li-Fraumeni syndrome to
1/1,000 for genes like BRCA1 and MLH1
(involved in DNA mismatch repair).
However, in some populations which have
arisen from a relatively small number of
founders, expanded rapidly and remained
genetically isolated, these genes can
achieve higher frequencies and therefore
account for a larger fraction of cancers. For
example, in the Jewish population, two specific
mutations (one in BRCA1, one in
BRCA2 ) are present. One in a hundred
Jewish individuals carry one of these two
mutations and they may account for as
much as 40% of all ovarian cancer cases
and 20% of all breast cancer cases diagnosed
under age 40 in this population.
Identification of genetically susceptible indi-
Genetic susceptibility
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