Recently, several studies have provided evidence that
p53 polymorphism at codon 72 may be associated with
certain tumors, such as cervical cancer, breast cancer, lung
cancer, and hepatocellular carcinoma. In particular, both
Arg and Pro alleles have been shown to be associated with
a high risk of malignancy. Indeed, an early involvement of
p53 in the progression from colonic dysplasia to invasive
colon cancer is suggested by the finding of mutated alleles
in the inflamed bowel mucosa of patients with ulcerative
colitis (UC) and cancer[
26].
Cancer is a multi-step mechanism occuring as a result
of series of progressive genetic alterations. So far, molecular
genetic studies revealed that a group of tumor supressor
gene and protooncogen alterations were effective
in cancer formation. p53 is the most important tumor supressor
gene that is effective in cancer formation and it is
very effective in progression of colon cancer. Due to this,
detection of p53 mutations are thought to be an important
factor in prognosis and early diagnosis. In this study, we
aimed to detect the frequency of mutations of p53, exon 4
Arg72Pro genotypes and their relations with progression
of the disease. Relevant to this, by PCR, amplification of
4th exon were performed from isolated DNA samples of
tumor tissues of colon cancer diagnosed in 35 cases and
mutation existence was tested by enzyme restriction. As a
result, the analysis of the p53 codon 72 genotype on the
DNA from the colon cancer tissues revealed 2 (5.7%) proline
homozygotes (Pro/Pro), 11 (31.4%) arginine/proline
heterozygotes (Arg/Pro), and 14 (40.0%) arginine homozygotes
(Arg/Arg).
In this study, we investigated p53 codon 72 polymorphism
in a different age, sex and tumor grade of colorectal
carcinoma in colon cancer cases. Considering tumor
tissue DNA, we found a significantly higher frequency
of 72Arg in colorectal tumors. There was an apparent association
of the Arg genotype with tumor progression.
Schneider-Stock et al.[14] found preferential mutation
of the Arg allele in a group of colorectal adenocarcinomas.
They also reported selective loss of the Pro allele in
tumors with loss of heterozygosity (LOH), resulting in a
positive association between Arg prevalence and Dukes
progression. The authors discarded the possibility of HPV
as a potential mechanism for the higher frequency of Arg
alleles in colorectal tumors and hypothesized that carcinogenic
exposure may selectively affect the p53 Pro allele in
the development of colon cancer.
The p53 gene is one of the most extensively studied
human genes because of its role as a tumor suppressor
gene. Its diverse functions include DNA binding, cell cycle
control, DNA repair, differentiation, genomic plasticity,
and apoptosis. Thus, the overall function of p53 is to
maintain genomic integrity as a whole, providing a protective
effect against tumorigenesis. Recent studies indicated
that the Arg allele is preferentially mutated and retained in
various human cancers arising in Pro/Arg heterozygotes.
These findings suggest that this polymorphism acts as an
intragenic modifier of mutant p53 behavior and has an
effect on the biological activity of p53[27]. Also, experimental
evidence suggests that the p53 protein is related
to cell aggressiveness and tumor metastasis[28]. Recent
studies have shown that a common polymorphism at codon
72 of the p53 gene results in two alleles, the arginine
(Arg) and proline (Pro) isoforms, which differ biologically
and biochemically[29]. In this sense, it appears that
this polymorphism may be associated with differential
susceptibility to cancer. Several studies conducted in different
countries reported significant associations between
p53 polymorphism and human cancer. However, the data
available for most cancers remain inconclusive, including
colorectal cancer[30].
In this study we evaluated the association between the
risk of developing colon cancer and the genotype at codon
72 by PCR and restriction enzyme digestion. The length
of fragments in our cancer group were similar to those
reported by other authors in Chinese population[27].
Buyru et al. (31) reported that the purpose of their
study was to investigate whether p53 Arg at position
72 would represent a risk factor for breast cancer in the
Turkish population. Their results indicate that individuals
carrying the arginine allele have a 3-fold increased
breast carcinoma risk compared to proline homozygotes.
Statistical analysis revealed a significant increase in the
presence of the Arg allele in Turkish colon cancer patients
when compared with controls indicating that the Arg allele
represents a high-risk polymorphism in breast cancer
in their study group. This finding is discordant with some
reports which have not found a difference in the frequency
of the Arg allele between colon cancer patients. Similar
inconsistency for the codon 72 alleles exists also for other
tumors[31]. In this study, the relationship among tumor
grade and Arg-Pro genotypes in our cancer group were
similar to those reported by other authors[14,24].
Perez et al.[32] reported that p53 codon 72 arginine
homozygous genotype may represent a genetic predisposing
factor for colon cancer development. However, further
studies are needed in order to elucidate the role of p53 codon
72 polymorphism in colorectal cancer. Frequencies in
our study are very close to the frequencies from La Plata,
Argentina and Spanish people[33]. Pérez et al.[32] reported
that 58.5% of the cases were Arg/Arg, 37.7% were
Arg/Pro and 3.8% were Pro/Pro. The corresponding frequencies
were 0.77 for the arginine allele and 0.23 for the
proline allele, which is consistent with our results.
Our study is in agreement with Schneider-Stock et
al.’s[14] study, in which considering tumor tissue DNA,
they found a significantly higher frequency of the 72Arg
in colorectal tumors. There was an apparent association
of the Arg genotype with tumor progression, with metastases
showing a bias toward the Arg genotype. There
was only one metastasis with Pro/Pro homozygous constitution. They explained that all allelic losses at codon
72 of p53 exon 4 were directed toward the loss of the
proline allele. They suggest that the preferential loss of
the 72Pro variant and/or mutations of 72Arg, also seen
in their study for colorectal cancer and colorectal liver
metastases, is of biologic significance. Thus, they tested
all tumors for p53 mutations. Indeed, tumors that had retained
the 72Arg allele often carried p53 mutations, with
the ‘‘gain-of-function’’ type occurring with remarkably
high frequency. Presence of Arg72 in the mutant allele or
preferential retention of Arg72 allele in the tumoral tissue
(Arg bias) provides a selective growth advantage to tumor
cells during the stage of tumorigenesis. In addition, the
TP53 codon 72 polymorphism has been reported to be associated
with colorectal tumor malignant potential, age of
onset and survival[14,32-34]. Further studies, therefore,
should be performed to analyze this potential role of the
TP53 polymorphism for colorectal tumor characteristics.
In summary, we found a preferential loss of the 72Pro
allele and mutations in the retained 72Arg in colorectal
cancer. Our results indicate that individuals carrying the
arginine allele may have increased colorectal carcinoma
risk compared to proline homozygotes. Further studies
should be performed to analyze the potential role of the
TP53 polymorphism for colorectal tumor characteristics.
ACKNOWLEDGMENTS
The study was supported by grants from the Science
Faculty of Afyon Kocatepe University Research Project
Commission and the project number is 042.FENED.03.
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