Invasive breast carcinoma - IARC

These modifications result in the intranuclear
accumulation of p53 and in its activation
as a transcription factors. Tw o
major signaling pathways can trigger
T P 5 3 activation. The first, and best characterized,
is the pathway of response to
DNA damage, including large kinases of
the phosphoinositol-3 kinase family such
as AT M (ataxia telangiectasia mutated)
and the cell-cycle re g u l a t o ry kinase
C H E K 2. Both of these kinases phosphorylate
p53 in the extreme N-term i n u s
(serines 15, 20 and 37), within the re g i o n
that binds to MDM2. The second is activated
in response to the constitutive
stimulation of gro w t h - p romoting signaling
cascades. The central regulator in
this pathway is p14ARF, the altern a t i v e
p roduct of the locus encoding the
cyclin-kinase inhibitor p 1 6 / C D K N 2 a.
p14ARF expression is activated by E2F
transcription factors, and binds to
MDM2, thus neutralizing its capacity to
induce p53 degradation. This pathway
may be part of a normal feedback cont
rol loop in which p53 is activated as a
cell-cycle brake in cells exposed to
h y p e r p roliferative stimuli {2267}.
Gene function
After accumulation, the p53 protein acts
as a transcriptional regulator for a panel
of genes that differ according to the
nature of the stimulus, its intensity and
the cell type considered. Broadly speaking,
the genes controlled by p53 fall into
t h ree main categories, including cellcycle
regulatory genes (WAF1, GADD45,
14-3-3S, CYCLING), pro - a p o p t o t i c
genes (FAS/APO1/CD95, KILLER/DR5,
AIF1, PUMA, BAX) and genes involved in
DNA repair (O 6 MGMT, MLH2). The p53
protein also binds to compoments of the
transcription, replication and re p a i r
machineries and may exert additional
controls on DNA stability through the
modulation of these mechanisms.
Collectively, the p53 target genes mediate
two type of cellular responses: cellcycle
arrest, followed by DNA repair in
cells exposed to light forms of genotoxic
stress, and apoptosis, in cells exposed
to levels of damage that cannot be efficiently
repaired. Both responses contribute
to the transient or permanent suppression
of cells that contain damaged,
potentially oncogenic DNA. In the
mouse, inactivation of Tp53 by homologous
recombination does not prevent
normal growth but results in a strong predisposition
to early, multiple cancers,
illustrating the crucial role of this gene as
a tumour suppressor {714}.
Mutation spectrum
The T P 5 3 gene is frequently mutated in
most forms of sporadic cancers, with
p revalences that range from a few percents
in cervical cancers and in malignant
melanomas to over 50% in invasive carc i-
nomas of the aero-digestive tract. Over
75% of the mutations are single base substitutions
(missense or nonsense), clustering
in exons 5 to 8 that encode the DNAbinding
domain of the protein. Codons
175, 245, 248, 273 and 282 are major
mutation hotspots in almost all types of
cancers. To g e t h e r, these codons contain
over 25% of all known T P 5 3 m u t a t i o n s .
Other codons are mutation hotspots in
only specific tumour types, such as codon
249 in hepatocellular carcinoma and
codon 157 in bronchial cancer. Mutation
p a t t e rns can differ significantly between
between diff e rent types cancers or
between geographic areas for the same
cancer type (as for example hepatocellular
carcinoma). These observations have
led to the concept that mutation pattern s
may reveal clues on the cellular or environmental
mechanisms that have caused
the mutations {1107}. In sporadic bre a s t
cancers, T P 5 3 is mutated in about 25% of
the cases. However, several studies have
re p o rted accumulation of the p53 pro t e i n
without mutation in up to 30-40% of invasive
ductal carcinoma in situ. The mutation
p a t t e rn is similar to that of many other cancers
and does not provide information on
possible mutagenic events. There is limited
evidence that the mutation pre v a l e n c e
is higher in BRCA1 mutation carriers.
G e rmline T P 5 3 mutations have been
identified in 223 families. Of these families,
83 match the strict LFS criteria, 67
c o r respond to the extended, LFL definition,
37 have a family history of cancer
that does not fit within LFS or LFL definitions
and 36 have germline mutations
without documented familial history of
cancer (IARC TP53 mutation database,
w w w. i a rc.fr/p53). The codon distribution
of germline T P 5 3 mutations show the
same mutational hotspots as somatic
mutations {1475}. The distribution of
inherited mutations that predisposes to
b reast cancer are scattered along exons
5 to 8 with relative "hotspots" at codons
245, 248 and 273, which are also commonly
mutated in somatic breast cancer.
In contrast, a total of 16 breast cancers
have been detected in 5 families with a
g e rmline mutation at codon 133, a position
which is not a common mutation
hotspot in somatic breast cancer. It
remains to be established whether this
mutant has particular functional pro p e r-
ties that predispose to breast cancer.
Genotype-phenotype correlations
Brain tumours appear to be associated
with missense TP53 mutations in the
Fig. 8.13 The p53 signaling pathway. In normal cells the p53 protein is kept in a latent state by MDM2.
Oncogenic and genotoxic stresses release p53 from the negative control of MDM2, resulting in p53 accumulation
and activation. Active p53 acts as transcription factor for genes involved cell cycle control, DNA
repair and apoptosis, thus exerting a broad range of antiproliferative effects.
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