When Lane and Crawford[
1] and Linzer et al.[
2] first
described p53 protein as a tumor antigen in 1979, they
probably never imagined that its gene would become
the most important tumor suppressor gene ever studied.
It took some time to realize that the p53 gene was a tumor
suppressor, not an oncogene, as was thought at the
beginning[
3-
8]. Frequent deletion of the 17p13.1 region
(p53 locus) was associated with mutation of the remaining
allele in a variety of tumors, including sporadic colon
cancer[
6,
9,
10].
Intronic variants may affect gene regulation through
aberrant splicing or through disruption of critical DNAprotein
interactions. The p53 G13964C variant is not
within the consensus splice site and there is thus far no direct
evidence that it affects the expression of p53. It is not
associated with over-expression of p53, which is a hallmark
of missense mutations in p53. Nonetheless, there is
some indirect evidence that this variant has a functional
role[11-13]. Functional analysis using an in vitro cell survival
assay demonstrated that lymphoblastoid cell lines
derived from patients with the G13964C variant exhibited
a reduced level of apoptosis after chemotherapy and
prolonged cell survival following DNA damage. The constitutional
p53 intronic G to C base change at nucleotide
13964 (GenBank accession number X54156/U94788),
was found by Buller et al.[14] in patients with ovarian
and breast cancer.
There is now substantial evidence that p53 gene abnormalities
are frequently associated with the pathogenesis
of neoplasias, particularly solid tumors, like breast,
lung and colon cancer[15]. The role of the p53 gene in
a variety of cellular processes, including transcription,
DNA repair, cell cycle control and apoptosis, makes it a
potential marker for the detection of patients at higher risk
for developing cancer[16]. Most of the reported mutations
in the p53 gene cluster within the region coding the
DNA-binding domain[17] impairing the DNA binding or
transactivation functions of the protein, thereby inhibiting
its key role in cell cycle control[18]. There is accumulating
evidence that novel mechanisms of gene regulation,
including mutations in the splice, donor and acceptor sites
or enhancer, intron and promoter elements, may be important
in regulating gene expression[19]. In addition to
the numerous coding region mutations, the p53 gene also
contains several polymorphisms and non-coding region
mutations. The regulatory role of intronic sequences has
been recognized only recently. Some germline polymorphisms
include a variable number of tandem repeat regions
in intron 1, various different RFLPs in introns 1, 6
and 7, a 16 bp insertion in intron 3 as well as transversions
in introns 2 and 10[20-25]. Among these, the intron 3
and intron 6 polymorphisms have been widely analyzed
as possible cancer susceptibility modifiers.
The G to C base change at intron 6 nucleotide 13964
of the p53 gene destroys a natural restriction site. The p53
G13964C variant is not within the consensus splice site
and there is thus far no direct evidence that it affects expression
of the p53 gene. Nonetheless, recent data suggests
a functional role for this variant leading to stabilization,
possibly inactivating the p53 protein, thereby
contributing to tumorigenesis[26].
In order to determine the importance of the G13964C
p53 variant in multiple-case Australian breast cancer
families, it has been genotyped this variant in the youngest
affected member of 71 breast cancer families and 143
control individuals. Researchers results suggest that the
rare 13964C allele is no more common in breast cancer
families than in control individuals. This suggests that the
variant is not a high-risk mutation but, as suggested previously,
is more likely to be a benign polymorphism[14].
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