p53 Codon 72 Polymorphism as a Risk Factor in the Development of HPV-Associated Cervical Cancer

doi:10.1006/mcbr.2000.0196

Molecular Cell Biology Research Communications

Volume 3, Issue 2, February 2000, Pages 111-114

https://doi.org/10.1006/mcbr.2000.0196 Get rights and content

Abstract

Human papilloma virus (HPV) has been implicated in cervical carcinoma, and the p53 gene is polymorphic at amino acid 72 of the protein that it encodes. The association between p53 polymorphisms and risk for HPV-associated cervical cancer has been examined, but the results have been conflicting. It has been reported that patients with the arginine form have a higher risk of developing cervical cancer than those with the proline form. The purpose of this study was to examine whether p53 Arg at the polymorphic position 72 could represent a risk factor for women with high-risk HPV-associated premalignant and malignant cervical lesions. The study was carried out on 60 smears from patients with high-risk HPV-related cervical lesions. Also, 74 HPV-negative normal smears and 61 normal blood samples were used as controls. HPV-18 was the most frequent type. There was a difference in the distribution of p53 genotypes between high-risk HPV-cervical lesions and the normal samples. The allele frequency of p53 Arg/Arg was much higher than the normal samples (46.5% versus 20.5% in HPV-negative normal smears and 20% in blood samples). Based on the findings of this study, it is suggested that p53 Arg homozygosity could possibly represent a potential risk factor for the tumorigenesis of the cervix. Statistically significant correlation was not observed between the presence of Arg/Pro homozygosity or Arg/Pro heterozygosity and HPV typing.

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Cited by (39)

The LIG4 Ile658Val polymorphism does not affect the risk of cervical carcinoma
2010, Pathology Research and Practice
The aim of this study was to investigate whether gene LIG4 genetic polymorphism affects the risk of cervical carcinoma. We studied 500 cervical carcinoma patients and 800 normal women as controls. Demographic and epidemiologic risk factors were recorded. Single nucleotide polymorphisms (SNPs) (LIG4 Ile658Val) were genotyped. Compared to LIG4 Ile658Ile (AA) genotype, LIG4 Ile658Val (AG) did not increase or decrease the risk of cervical carcinoma or cervical squamous cell carcinoma [ORs and 95% CIs being 1.07 (0.70–1.63) and 1.01 (0.65–1.55)], while no homozygous LIG4 Val658Val (GG) was found in the cervical carcinoma group. Analyzing the risk of variant LIG4 Ile658Val genotypes for cervical carcinoma of different histologic types or HPV infection status, we found striking similarities between the squamous cell carcinoma group and the HPV-positive group and the overall carcinoma. In conclusion, in the Chinese population, LIG4 Ile658Val has only a slight impact on the risk of developing cervical carcinoma.
p53 Codon 72 polymorphism is associated with occurrence of cervical carcinoma in the Chinese population
2010, Cancer Letters
Citation Excerpt :
To date, nearly 50 investigations about the relationship of this polymorphism to cervical disease have been reported [4–7]. However, only a few studies have reported consistent results [8–11] that homozygosity of Arg at codon 72 conferred susceptibility to cervical cancer. Lack of the evaluation of these complex gene–environment interactions as well as gene–gene interactions may have contributed to the inconsistency in the previous results.
We investigated the genotype distribution of the p53 Arg72Pro polymorphisms in 500 cervical carcinoma and 800 normal women in Chinese population. HPV infection rates in carcinoma patients and control were 89.4% and 31.0%. Women carrying the p53 Arg72Pro or p53 Pro72Pro increased the risk of cervical carcinoma (ORs and 95% CIs being 3.74 (2.65–5.30), 2.23 (1.49–3.34)). In HPV positive population, elevated risks were also associated with p53 Arg72Pro, Pro72Pro (ORs and 95% CIs being 3.83 (2.02–7.24), 2.38 (1.14–4.99)). These results suggest that a proline in position 72 of p53 increases the risk of cervical carcinoma in Chinese population.
TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies
2009, The Lancet Oncology
Citation Excerpt :
Subsequently, more than 80 studies have been published on this issue, with widely inconsistent results. Only one study quantitatively supported the initial findings of Storey and colleagues,18 other studies also found an increased risk,19–21 while many did not.22–26 Two meta-analyses based on early studies and published data only found significant associations with squamous-cell carcinoma27 or adenocarcinoma.28
Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer.
Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy–Weinberg equilibrium, study quality, and the material used to determine TP53 genotype.
The pooled estimates (OR) for invasive cervical cancer were 1·22 (95% CI 1·08–1·39) for arginine homozygotes compared with heterozygotes, and 1·13 (0·94–1·35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy–Weinberg equilibrium (1·71 [1·21–2·42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1·35 [1·15–1·58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1·39 [1·13–1·73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1·06 [0·87–1·29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1·06 [0·87–1·29] for arginine homozygotes compared with heterozygotes).
Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.
German Research Foundation (DFG).
P53 Codon 72 polymorphisms: A case-control study of gastric cancer and potential interactions
2006, Cancer Letters
P53 codon 72 polymorphisms have been reported to be associated with cancers of the lung, esophagus and cervix. However, there have been no reports on the interaction of select risk factors and p53 codon 72 polymorphisms in gastric cancer susceptibility. 155 gastric cancer cases and 134 cancer-free controls were enrolled at the Memorial Sloan Kettering Cancer Center (MSKCC) from November 1992 to November 1994. The crude odds ratio (OR1) associated with the (Pro/Pro) polymorphism and the risk of gastric cancer was 1.27 (0.70–2.33). Adjusting for age, sex, race and education (OR2) and further adjusting for BMI, calories, sodium, smoking, vitamin C, fiber, alcohol, fat, and H. pylori status (OR3) did not yield significant results. Significant joint effects were associated with high fat consumption (OR1=2.61 (95% CI:1.13–6.06); OR2=2.85 (95% CI:1.14–7.15) for total cancers and for proximal tumors (OR1=2.56 (95%CI:1.00–6.54)). The low vitamin C intake/high-risk polymorphism group (Pro/Pro) had an OR1 of 4.82 (95% CI: 1.72–13.45) and the OR2 was 6.19 (95% CI: 2.08–18.40) for distal tumors. The point estimates were increased for interaction odds ratios but not statistically significant (OR1=4.25 (95% CI: 0.66–27.50); OR2=4.73 (95% CI: 0.67–33.43); OR3=5.55 (95% CI: 0.66–46.47)). Further studies specifically looking at proximal and distal tumors are required to confirm any potential interaction between the p53 codon 72 polymorphisms and environmental risk, in particular low dietary vitamin C and high fat consumption.
Polymorphism p53 codon-72 and invasive cervical cancer: A meta-analysis
2004, International Journal of Gynecology and Obstetrics
Objectives: Although some studies have reported that the arginine isoform on codon 72 of p53 increases the susceptibility to invasive cervical cancer, such data remain controversial. The objective of this study was to quantitatively summarize the evidence for such a relationship. Methods: Our data sources consisted of a MEDLINE search of the literature published before December 2002, bibliography review, and expert consultation. Thirty-seven studies met the inclusion criteria. Information on sample size, study design, Hardy–Weinberg equilibrium, and method of genotype determination was abstracted by two reviewers using a standardized protocol. The overall odds ratio (OR) of the p53 gene on invasive cervical cancer was estimated using the Mantel–Haenzel method. Results: The overall OR (95% confidence interval) for cervical cancer among those with the homozygous mutant (Arg/Arg) was 1.2 (1.1–1.3, P=0.001) compared with those with the heterozygous mutant (Arg/Pro). By a cellular type of cervical cancer, the overall OR among those with Arg/Arg was statistically significant in adenocarcinomas (1.7, 1.1–2.6, P=0.024), but not in squamous cell carcinomas (1.1, 0.9–1.2, P=0.960), compared with Pro/Pro. Compared with Arg/Pro, the OR among those with Arg/Arg was statistically significant in HPV types 16 (1,5, 1.2–2.0, P=0.002). Conclusions: Overall, the p53 gene was associated with increased risk for invasive cervical cancer. However, the risk varied by country, cellular, and HPV type.
Genetic susceptibility for cervical cancer in African populations: What are the host genetic drivers?
2018, OMICS A Journal of Integrative Biology

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Regular Articlep53 Codon 72 Polymorphism as a Risk Factor in the Development of HPV-Associated Cervical Cancer

Abstract

Gene

Cell

Am. J. Obstet. Gynecol.

J. Invest. Dermatol.

Blaustein's Pathology of the Female Genital Tract

Annu. Rev. Microbiol.

Mol. Cell. Biol.

Nucleic Acids Res.

Cancer Res.

Nature

Regular Article
p53 Codon 72 Polymorphism as a Risk Factor in the Development of HPV-Associated Cervical Cancer