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p53 alterations in human cancer: more questions than answers

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The spectrum of p53 mutations is not a strong argument to infer neomorphic or antimorphic mutations Unlike most other tumour suppressor genes that are inactivated by frameshift or nonsense mutations leading to disappearance or aberrant synthesis of the gene product, almost 80% of p53 gene muta...

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p53 alterations in human cancer more questions th
the spectrum of p53 mutations is not a strong argu

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Oncogene (2007) 26, 2145–2156
& 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00
www.nature.com/onc

REVIEW

p53 alterations in human cancer: more questions than answers

T Soussi1,2
1
Department of Life Sciences, Université Pierre et Marie Curie-Paris, Paris, France and 2Department of Oncology-Pathology, Cancer
Center Karolinska (CCK), Karolinska Institute, Stockholm, Sweden

The strongest and undisputed fact about p53 is the high related to involuntary cloning of mutant p53, this
frequency of p53 alterations in human cancer and that ambiguity is also due to our propensity to over
mutant p53 proteins constitute a complex family of several categorize in order to satisfy our Cartesian and over-
hundred proteins with heterogeneous properties. Beyond simplistic view of science.
these observations, the p53 pathway and its regulation in a In fact, review of a number of old publications
normal cell is like a desert trail, always moving with the combined with novel data clearly show that wild-type
wind of novel findings. The field is full of black boxes that p53 cannot be confined to the single category of tumour
are often ignored for sake of simplicity or because they do suppressor gene and that mutant p53 is not a single
not fit with the current dominant view. Mutant p53 protein entity, but a complex collection of proteins, each with a
accumulation in tumours is the best example of a unique set of properties defined by a combination of
preconceived idea, as there is no experimental evidence heterogeneous loss of activity, dominant-negative acti-
to explain this observation. In this review, we will discuss vity (antimorphic) and gain of function (neomorphic).
several questions concerning the activity or selection of Several layers of complexity can also be added to
p53 mutations. The central domain of the p53 protein mutant p53 function by arguing that tissue specificity or
targeted by 80% of p53 mutations is associated with the tumour genetic background can also modulate their
DNA-binding activity of the p53 protein, but it is also the function.
binding site for several proteins that play a key role in p53 One of the advantages of an invited review is the
regulation such as ASPP proteins or BclxL. The role of freedom to approach various topics that are not always
impaired DNA binding and/or protein interactions in open for discussion and to raise questions that I
tumour development has not been fully elucidated. personally feel are either biased by dominant-precon-
Similarly, novel animal models carrying either missense ceived ideas and/or underestimated due to lack of
p53 mutations or inducible p53 have provided abundant interest. The explanation for p53 accumulation in
observations, some of which could challenge our view on tumour cells is a perfect example (see below). As insight
p53 function as a tumour suppressor gene. Finally, the is obtained from discussions and exchanges, all ques-
possible clinical applications of p53 will be discussed. tions raised in this review will be available as topics for
Oncogene (2007) 26, 2145–2156. doi:10.1038/sj.onc.1210280 discussion in the p53 forum that will open in Spring
2007.
Keywords: p53 mutations; apoptosis; cancer; cell cyle;
tumour suppressor gene
The spectrum of p53 mutations is not a strong argument
to infer neomorphic or antimorphic mutations
y.These results demonstrate that p53 can be activated
by mutational changes in the cellular gene and suggest Unlike most other tumour suppressor genes that are
that mutation leading to an increased stability of a inactivated by frameshift or nonsense mutations leading
short half-life protein is a novel mechanism by which a to disappearance or aberrant synthesis of the gene
cellular oncogene can participate in multistage carcino- product, almost 80% of p53 gene mutations are missense
genesis. mutations leading to the synthesis of a stable protein,
Jenkins et al. (1985) Nature 317: 816–818. lacking its specific DNA-binding activity and accumulat-
The history of p53 is a chaotic voyage from the world of ing in the nucleus of tumour cells (Soussi, 2005).
oncogenes to the world of tumour suppressor genes, Whether this high frequency of missense mutations is
while retaining a certain degree of individuality (Lane specific for the p53 gene during tumourigenesis or
and Benchimol, 1990). Apart from artefactual problems corresponds to the normal pattern of mutation in human
cancer is difficult to assess. However, the recent analysis
of the genome of colorectal and breast cancer may shed
new light on this question. Sequencing of more than
Correspondence: Professor T Soussi, Department of Oncology-
Pathology, Cancer Center Karolinska (CCK), Karolinska Institute, 13 000 genes in eleven breast and colorectal tumours led
Stockholm SE-171 76, Sweden. to the detection of 1672 mutations (Sjoblom et al., 2006).
E-mail: As the sequencing strategy did not specifically focus on

, p53 alterations in human cancer
T Soussi
2146
oncogenes or tumour suppressor genes, we can expect mutation in human cancer with 80% of missense
that the spectrum of mutations will reflect a general mutations, 10% of insertions/deletions and 8.8% of
mutagenesis mechanism. First of all, for both colorectal missense mutations. This figure is observed for both
and breast cancer, the frequency of missense mutations the entire p53 database (2006 version comprising 24, 151
was 80%: 7% were nonsense, 4% were splice mutations mutations) and for breast or colorectal cancer (Figure 1).
and 8% were insertions and deletions (Figure 1). This On the other hand, this pattern is totally different
figure is strikingly similar to the spectrum of p53 from those observed for other oncogenes or tumour

Figure 1 Mutational spectrum of the TP53 gene in human cancer: (a) frequency of missense, nonsense and frameshift mutations: Can-
Genes, data obtained by Sjoblom et al. (2006), for colorectal cancer (CRC), breast and both (All). p53 data obtained from the UMD
p53 database (http://p53/free/fr) for all cancers (All), breast and CRC. Rb: data from the retinoblastoma database; NF2: data from the
type 2 Neurofibromatosis database; VHL: data from the Von Hippel Lindau mutation database; PTCH: data from the xx mutation
database; APC: data from adenomatous polyposis coli mutation database. (b) Pattern of mutational events in CRC and breast cancer
from the Can-Genes study (left) and p53 mutation database (right). Data for oncogenes have not been included as most of them lead to
the detection of more than 90% of missense mutations.

Oncogene

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