Glutathione-S-transferase and p53 polymorphisms in cervical carcinogenesis

OBJECTIVE: To investigate the clinical significance of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in cervical carcinogenesis. METHODS: GSTM1, GSTT1 and p53 codon 72 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 198 cervical smear samples using multiplex polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (RFLP) techniques. RESULTS: Forty-two patients with high-grade squamous intraepithelial lesion (HSIL) had higher frequency of high-risk HPV and null GSTT1 genotype than 102 with low-grade SIL (LSIL) and 54 controls. Thirty-one patients with HSIL had also statistically higher frequency of null GSTT1 genotype than 28 with LSIL among 69 patients with high-risk HPV. There was no statistical difference in p53 Arg, Arg/Pro and Pro genotypes between SILs and controls with or without high-risk HPV. CONCLUSION: GSTT1 null genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population. The p53 codon 72 polymorphism is unlikely to be related to HPV status and the onset of cervical cancer.     

CYP1A1, GSTM1, and GSTT1 polymorphisms and the risk of cervical squamous intraepithelial lesions in a multiethnic population

OBJECTIVE: In this investigation, we explored the hypothesis that genetic polymorphisms in the cytochrome P4501A1 (T3801C) and glutathione S-transferase classes mu and theta (GSTM1 and GSTT1) gene deletions promote the development of cervical dysplasia by moderating the activation and detoxification of polycyclic hydrocarbons and other compounds that influence oxidative stress and DNA adduct formation. METHODS: A multiethnic, case-control study of 131 women with biopsy-confirmed cervical squamous intraepithelial lesions (SIL) and 180 controls with cytologically normal cervical (Pap) smears was conducted between 1992 and 1996 in Honolulu, Hawaii. We collected in-person interviews, a blood sample to extract genomic DNA, and an exfoliated cervical cell sample to determine the presence and type of human papillomavirus (HPV) using PCR dot-blot hybridization. Genotyping for the CYP1A1 MspI allelic variant and deletion of the GSTM1 and GSTT1 gene loci followed a PCR method. RESULTS: Women who were homozygous, but not heterozygous, for the CYP1A1 MspI variant allele were at significantly increased risk of cervical SIL (odds ratio (OR) = 3.4; 95% confidence interval (CI) = 1.1-10.7) compared to women who were homozygous for the wild-type allele. Subjects with the GSTM1 null genotype had a nonsignificant elevated risk of cervical SIL (OR = 1.6; 95% CI = 0.8-3.0) compared to women with the gene present. No difference in the risk of cervical disease was associated with the GSTT1 null genotype. The combination of the CYP1A1 homozygous variant and the GSTM1 null genotypes increased the odds ratio for cervical SIL to 5.1 (95% CI = 1.3-20.7). There was no evidence for an interaction between genotype and exposure to tobacco smoke, alcohol drinking, or HPV DNA positivity. CONCLUSIONS: These findings, although based on a small number of subjects, suggest that the CYP1A1 MspI polymorphism may be a susceptibility factor for early, premalignant changes in the cervical epithelium.     

Lack of evidence that proline homozygosity at codon 72 of p53 and rare arginine allele at codon 31 of p21, jointly mediate cervical cancer susceptibility among Indian women

OBJECTIVES: The objective of this study was to identify whether variants of p53Arg72Pro and p21Ser31Arg were associated with increased risk for cervical cancer (CaCx), either independently or jointly, among Indian women. METHODS: Genotyping was done by PCR-RFLP using DNA from (i) 120 cervical biopsy tissues of squamous cell carcinoma of the cervix (of which 82 were HPV16/18 positive), and (ii) a total of 205 cytologically normal cervical scrapes (121 HPV-negative and 84 HPV16/18-positive samples, considered as discreet groups). Multiple logistic regression analyses were performed to examine additive or interactive effects of the two factors and for determining age-adjusted OR (95% CI) and P values. RESULTS: The observed association of proline homozygosity at codon 72 of p53 with CaCx infection (Bhattacharya, P., Duttagupta, C., Sengupta, S. 2002.Proline homozygosity in codon 72 of p53: A risk genotype for Human Papillomavirus related cervical cancer in Indian women. Cancer Lett 188: 207-211) was retained among Indian women harboring HPV16/18 (OR(age-adjusted) = 3.76; 95% CI = 1.03-13.80; P = 0.04). Significant independent association was evident between the p21 arginine allele (rare allele with frequency of 0.1) at codon 31 and CaCx, compared to HPV-negative cytologically normal controls (OR(age-adjusted) = 2.01; 95% CI = 1.00-4.06; P = 0.05). The two risk factors jointly failed to show statistical interaction towards susceptibility to CaCx. The p21 arginine allele was significantly associated with CaCx in the p53 proline non-homozygous group of subjects (OR(age-adjusted) = 2.68; 95% CI: 1.21-5.91; P = 0.01), and specifically in the p53 heterozygous group (OR(age-adjusted) = 2.91; 95% CI = 1.12-7.56; P = 0.03). CONCLUSIONS: p53 and p21 act in series in mediating cell cycle arrest. However, the two risk factors, p53 proline homozygosity and p21 arginine allele, although part of a common causal pathway, appear to act in a mutually exclusive manner.     

Association of the NAD(P)H: quinone oxidoreductase C609T polymorphism and the risk of cervical cancer in Japanese subjects

OBJECTIVE: In this study, genetic polymorphisms, NQO1 C609T, GSTM1 positive/null, and GSTT1 positive/null, were examined with reference to cervical cancer risk in a population-based incident case-control study in Japanese. METHODS: The cases comprised 131 cervical cancer patients: 87 cases with squamous cell carcinoma (SCC) and 44 with adenocarcinoma (ADC) or adenosquamous carcinoma (ADSC). Controls were sampled from 320 healthy women who underwent a health checkup. RESULTS: The cervical cancer risk was substantially elevated with smoking for all cases, SCC cases, and ADC/ADSC cases (OR = 4.50, 95% CI = 2.48-8.17, P < 0.001; OR = 5.68, 95% CI = 2.99-10.78, P < 0.001; and OR = 2.57, 95% CI = 1.09-6.08, P = 0.032; respectively). The frequency of the NQO1 609TT genotype, reported to be associated with null enzyme activity, was higher in individuals with all cases and SCC than in the healthy controls (OR = 1.97, 95% CI = 1.06-3.66, P = 0.032; and OR = 2.42, 95% CI = 1.21-4.82, P = 0.012; respectively), but not in ADC/ADSC cases. Analysis of polymorphisms for GSTM1 and GSTT1 showed no significant differences between cervical cancer patients and controls. In stratification analysis, significant elevated risk of all cases and SCC was associated with the NQO1 609TT genotype among nonsmokers (OR = 2.15, 95% CI = 1.08-4.30, P = 0.030; and OR = 2.83, 95% CI = 1.21-6.31, P = 0.011; respectively), but not smokers. No gene-gene interaction was observed in our case subjects. CONCLUSION: This is the first report that the NQO1 gene might be important in relation to the risk of squamous cell carcinoma of the cervix.     

Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer: association with p53 expression and survival

Abstract. The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models.
Performance status ( P < 0.001), operative stage ( P = 0.004), residual disease ( P = 0.001), histologic subtype ( P = 0.05), tumor grade ( P = 0.007), and the combined GSTMI null/GSTTl null genotype ( P = 0.023) were all individually associated with survival. p53 expression was not associated with survival ( P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy ( P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.     

Germline polymorphism of p53 codon 72 in gynecological cancer

OBJECTIVE: To investigate the biological significance of single nucleotide polymorphism at codon 72 of the p53 gene in the development of gynecological cancer. METHODS: p53 codon 72 polymorphism was examined in a total of 354 blood samples from 95 normal, 83 cervical, 108 endometrial and 68 ovarian cancer cases using polymerase chain reaction and restriction fragment length polymorphism techniques. RESULTS: When p53 codon 72 genotype was classified into two subgroups of Arg/Arg and Arg/Pro + Pro/Pro, the Arg/Arg genotype was associated with an increased risk for the development of endometrial cancer (OR = 1.86, 95% CI = 1.06 to 3.26) compared with the Arg/Pro + Pro/Pro genotype (P = 0.0301). The Arg allele also increased the risk of endometrial cancer (OR = 1.42, 95% CI = 0.93 to 1.52) compared with the Pro allele, but no statistical difference was found (P = 0.1031). There was no significant difference in the genotype or allele prevalence between control subjects and cervical or ovarian cancer patients. CONCLUSION: Homozygous Arg at codon 72 of the p53 gene may be a risk factor for developing endometrial cancer in a Japanese population.     

HPV16/18 prevalence in cervical lesions/cancers and p53 genotypes in cervical cancer patients from India

OBJECTIVES: The HPV16/18 code for an oncoprotein-E6, which binds to p53 tumor suppressor protein and degrades the protein via ubiquitination. A common polymorphism of p53 in exon 4 codon 72, resulting in either proline (Pro) or arginine (Arg), affects HPV16/18 E6-mediated degradation of p53 protein in vivo. Hence, in the current study we investigated the prevalence of HPV16/18 in cervical lesions and the distribution of p53 genotypes in cervical cancers and normal healthy women. METHODS: DNA from 337 Indian women with invasive cervical cancers, 164 women with clinically normal cervix, 64 women with low-grade squamous intraepithelial lesions (LSIL), and 5 women with high-grade squamous intraepithelial lesions (HSIL) was examined for the presence of HPV16/18 using consensus primers in a polymerase chain reaction (PCR), and the specific HPV type was identified by Southern hybridization of the PCR product using HPV16/18 type-specific nucleotide sequences as probes. Further, 134 women with cervical cancers and 131 healthy women were used to determine the frequency of p53 genotypes, Pro/Pro, Arg/Arg, and Pro/Arg, using peripheral blood cell DNA to indicate the constitutional genotypes and allele-specific primers, in a PCR-based assay. RESULTS: We observed a prevalence of HPV16/18 in 77% (258/337) of cervical cancer patients, 38% (24/64) of LSILs, 4 of 5 HSILs, and 15.2% (25/164) of normal healthy women. The frequency of distribution of the three genotypes of p53 codon 72 in a subgroup of the HPV16/18-positive cervical cancer patients was Pro/Pro 0.18 and Arg/Arg 0.26, with the heterozygous Pro/Arg 0.56, differing significantly from the genotype frequency in the normal healthy women (chi(2) = 6.928, df = 2, P < 0.05). CONCLUSIONS: A high prevalence of HPV16/18 was observed in the cervical cancers. The prevalence in LSILs confirms HPV16/18 infection as an early event and further indicates a role in progression of lesions. The p53 genotype distribution indicated that women homozygous for Arg genotype were at a 2.4-fold higher risk for developing HPV16/18-associated cervical carcinomas, compared to those showing heterozygous Pro/Arg genotype (odds ratio 2.4, 95% confidence interval 1.89 to 3.04).     

Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: associations with tumor progression, age and human papillomavirus infection

OBJECTIVES: Host genetic factors may play a role in human papillomavirus (HPV)-associated tumorigenesis, although the issue continues to be a focus of much debate. Biotransformation is critical in carcinogenic activity of numerous environmental carcinogens. It is therefore possible that polymorphisms of genes producing functional changes in xenobiotic metabolizing enzymes may be susceptible factors in cervical carcinogenesis. This study looked into possible relationships among these factors. METHODS: In this case-control study, we analyzed leukocyte DNA from a total of 312 subjects for germline polymorphisms of CYP1A1 (m1 and m2), GSTM1 and GSTT1 at various stages of the cervical tumor progression spectrum, using PCR and RFLP. RESULTS: Both m1 and m2 polymorphisms of the CYP1A1 gene were more frequent among cases (36.1% for m1 and 38.1% for m2) compared to control subjects (18.2% and 17.6% respectively). The odds ratio of a subject with homozygous CYP1A1 m1 and m2 variant being a case was highest (m1 OR = 4.77 [95% CI = 1.28-17.77]; P = 0.02 and m2 OR = 5.48 [95% CI = 1.49-20.19]; P = 0.011) respectively. The distribution of m1 and m2 CYP1A1 genotypes was also studied as a function of age and in relation to the presence of HPV 16 infection. The risk due to CYP1A1 m1 genotype, when adjusted for HPV status, showed a significantly increased risk (OR = 3.58, 95% CI = 1.88-6.81; P = 0.0001). Similar results were observed in the case of CYP1A1 m2 variant and HPV 16. There was a significant over-representation of both m1 (25.9% vs. 13.9%) and m2 (27.9% vs. 13.3%) polymorphisms in older women (46 years or more). GSTM1 and GSTT1 deletions were also prominent among cases (53.7% and 16.3% respectively) compared to controls (32.7% and 9.7% respectively). A higher proportion of both GSTT1 and GSTM1 deletions were also detected in HPV-16-positive subjects. CONCLUSIONS: These results suggest that polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes may render women more susceptible to the development of cervical cancer. The association between this susceptibility and the presence of human papillomavirus infection further emphasizes the significance of the genetic polymorphisms.     

p53 at codon 72 polymorphism, human papillomavirus infection and cervical lesions: a cross-sectional study from northeastern Italy

OBJECTIVE: To test the hypothesis that p53 homozygous Arg/Arg genotype at codon 72 is a significant risk factor for the development of HPV induced cervical cancer. STUDY DESIGN: A cross-sectional survey on p53 allelotypes distribution in women with different grade of cervical lesions and with or without HPV infection, in comparison to the distribution on a control group of women cytologically normal and HPV negative. RESULTS: No statistically significant difference in the p53 polymorphism distribution was found in relation to the infection with HPV, the cytological pattern and both conditions. A modest but constant over-representation of Pro-allelotypes was found in all groups in comparison to the control group. CONCLUSION: Searching for p53 polymorphism in a clinical setting does not seem to support secondary prevention procedures, at least for women in this area.     

GSTM1、CYP2E1基因多态性与新疆维吾尔族妇女宫颈癌及癌前病变关联性的研究

目的:探讨谷胱甘肽硫转移酶基因GSTM1和细胞色素氧化酶P4502E1(CYP2E1)的基因多态性与新疆维吾尔族妇女宫颈癌前病变与癌的关联性。方法:用聚合酶链反应(PCR)方法及聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法为21例浸润性宫颈癌(ICC)、41例宫颈上皮内瘤变(CIN)及45例慢性宫颈炎标本进行GSTM1和CYP2E1RsaⅠ位点基因分型。结果:ICC组和CIN组的GSTM1空白基因型频率明显高于慢性宫颈炎组(对照组),差异有统计学意义(χ2=7.56,P<0.05;χ2=13.30,P<0.05),携带GSTM1(-)的个体患宫颈癌的危险性比携带GSTM1(+)的个体升高3.47倍(OR=4.47,95%CI=1.5～13.0),患CIN的危险性升高4.30倍(OR=5.30,95%CI=2.2～13.0)。CYP2E1基因RsaⅠ位点多态在3组的频率差异无统计学意义(χ2=2.28,P>0.05)。联合分析3组病例CYP2E1基因RsaⅠ多态性和GSTM1基因多态性,未发现两者之间的交互作用与ICC及CIN易感性有关(χ2=4.47,P>0.05)。结论:GSTM1基因空白型可能与维吾尔族宫颈癌及癌前病变风险增加有关,CYP2E1基因RsaⅠ多态性与宫颈癌及癌前病变无关。     

Combined effect of GSTT1 and GSTM1 polymorphisms on human male infertility in north Indian population

Genes of different pathways regulate spermatogenesis, and complexity of spermatogenic process indicates that polymorphisms or mutations in these genes could cause male infertility. Detoxification pathway is involved in the regulation of spermatogenesis by reducing oxidative stress and contributes to the maintenance of global methylation in concert with other pathways. Glutathione S-transferases (GSTs) belong to the family of phase II antioxidant enzymes involved in the cellular detoxification of various physiological substances. Glutathione S-transferases act as an antioxidant and protect spermatozoa from oxidative stress. Increase in the levels of reactive oxygen species (ROS) along with reduced activity of GSTs may result in sperm membrane damage and DNA fragmentation. A case-control study was done to elucidate the role of deletion polymorphism of GSTT1 and GSTM1 genes from GSTs family on idiopathic human male infertility. The study comprises 2 groups: 113 nonobstructive azoospermia patients and 91 healthy fertile controls. Genomic DNA was analyzed by polymerase chain reaction for GSTT1 and GSTM1 genes. The study showed statistically significant protective association of GSTT1 null genotype with human male infertility (odds ratio [OR]: 0.3, 95% confidence interval [CI] 0.143-0.9966, P = .048) but not with GSTM1 null genotype (OR: 0.66, 95% CI 0.3653-1.2234, P = .19). Also, combination of null genotypes of GSTM1 and GSTT1 confers protective effect (OR: 0.28, CI 0.0801-0.948; P = .04). Probably, individuals bearing GSTM1 and GSTT1 (-/-) genotypes may have protective effect by gene-gene interaction mechanism. In summary, our study underscores the significance of combined effect of GSTT1 and GSTM1 null genotypes in modulating the risk of male infertility.     

Polymorphism p53 codon-72 and invasive cervical cancer: a meta-analysis.

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.     

Glutathione-S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis in Chinese populations

Abstract

In view of the controversies surrounding the glutathione-S-transferases (GST) M1/T1–endometriosis association, a meta-analysis of the GSTM1/GSTT1 genetic association studies of endometriosis was performed in Chinese populations. PubMed, Springer Link, OvidSP, and Chinese databases were searched for related studies. A total of nine studies on GSTM1-endometriosis involved 874 cases and 997 controls, and five studies on GSTT1 involved 404 cases and 513 controls were included in this meta-analysis. Overall, the null genotype of GSTM1/GSTT1 was significantly related to endometriosis risk in Chinese populations (GSTM1, OR?=?2.21, 95% CI: 1.22–4.01; GSTT1, OR?=?2.31, 95% CI: 1.34–3.99). In subgroup analyses stratified by ethnicity and source of controls, the same results were observed in Chinese Han and population-based studies. The sensitivity analysis confirmed the reliability and stability of the meta-analysis. No publication bias was found among studies by Egger’s test. In conclusion, our meta-analysis supports that the GSTM1/GSTT1 null genotype might contribute to individual susceptibility to endometriosis in Chinese populations, especially in Chinese Han.     

p53 Polymorphism (codon-72) has no correlation with the development and the clinical features of cervical cancer

Abstract. Nishikawa A, Fujimoto T, Akutagawa N, Iwasaki M, Takeuchi M, Fujinaga K, Kudo R. p53 polymorphism (codon-72) has no correlation with the development and the clinical features of cervical cancer.
Recent analysis of the codon-72 polymorphism of the p53 gene, the allele encoding proline or arginine, suggested that the homozygous Arg/Arg genotype is a significant risk factor for cervical cancer associated with human papillomavirus (HPV). We investigated the polymorphism of p53 in cervical condylomas, cervical intraepithelial neoplasias (CINs), and cervical cancers, evaluating clinical implications of the polymorphism of p53 in development of cervical neoplasms. DNA from 87 cervical cancer tissues, 28 CIN tissues, and seven cervical condyloma tissues were examined for the presence of HPV DNA by the consensus PCR method and the p53 polymorphism was analyzed by PCR using an allele-specific primer. The frequencies of p53Pro, p53Arg, and p53 Pro/Arg were 14.3%, 57.1%, and 28.6% in condyloma patients; 21.4%, 39.3%, and 35.7% in CIN patients; and 10.3%, 44.8%, and 42.5% in cervical cancer patients, respectively. No statistically significant differences in the distribution of p53 genotypes were found among the patients with these diseases, regardless of HPV status. Furthermore, there was no clear correlation between the polymorphism of p53 and age, histopathologic type, clinical stage, or lymph node metastasis. Nor was there any evidence of a correlation between the p53 genotype and the outcome for patients with HPV-positive uterine cervical cancer.     

p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer

OBJECTIVE: Recently, there has been considerable interest in the association of specific cancers with single nucleotide polymorphisms (SNPs). In this regard, genetic polymorphism at codon 72 (CCC/proline to CGC/arginine [Pro(72)Arg]) of the p53 gene is one of the most frequently studied subjects. An association between endometrial cancer and the polymorphism at codon 31 (AGC/serine to AGA/arginine [Ser(31)Arg]) of the p21 gene, which is known to be a downstream mediator of p53, has also been reported. METHODS: The authors designed a hospital-based case-control study of 95 endometrial cancer patients and 285 non-cancer controls. For the determination of p53 and p21 polymorphism, allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism assay was applied, respectively. RESULTS: We found statistically significant differences in the frequency of the p53 and p21 genotypes between these two groups (P < 0.001), respectively. The p53 genotypes containing the Pro allele were significantly associated with endometrial cancer with an odds ratio (OR) of 3.56 (95% confidence interval [CI] 2.10-6.04). Also, homozygous carriers of the p21 Ser allele showed a substantially increased risk of developing endometrial cancer (OR 2.68, 95% CI 1.59-4.51) as compared to homozygous and heterozygous carriers of the Arg allele. In addition, the combination of the pro allele containing genotypes of p53 and the Ser homozygous genotype of p21 posed a remarkably increased risk (OR 9.55, 95% CI 4.30-21.24) of endometrial cancer development. These significant differences were maintained throughout the groups after they were stratified by menopausal status. CONCLUSIONS: These data suggest that there is a significant association between the genetic polymorphisms of p53, p21, and specific combinations of the at-risk genotypes of these genes and the risk of developing endometrial cancer in Korean women.     

Glutathione S-transferase M1 and T1 gene polymorphisms in Brazilian women with endometriosis

Purpose

The glutathione family (GST) genes appear to play a role in the genesis of endometriosis. This case–control study aimed to compare the frequencies of GSTM1 and GSTT1 polymorphisms in women with endometriosis and women without endometriosis.

Methods

Polymerase chain reaction was performed to analyze the GSTM1 and GSTT1 genotypes among women with surgically and histologically confirmed endometriosis (case group n = 121) and in women without evidence of endometriosis confirmed by laparoscopy for investigation the infertility or for laparoscopic tubal sterilization (control group n = 97).

Result(s)

No differences in the frequencies of GSTM1 polymorphism (null genotype) were observed between the cases and controls: odds ratio (OR) = 1.13; 95 % CI 0.656–1.93 (p = 0.659). The GSTT1 polymorphism (null genotype) was more prevalent in the endometriosis group than in the control group (OR = 0.53; 95 % CI 0.94–0.29 (p = 0.039). No relationship between menstrual cycle interval and GSTM1 null genotype frequency was observed in either cases or controls (p = 0.370 and p = 0.664, respectively). In addition, no relationship between menstrual cycle interval and GSTT1 null genotype was observed in cases (p = 0.797) or controls (p = 0.052).

Conclusions

GSTM1 null genotype frequency was similar between cases and controls. The GSTT1 null genotype was more frequent in the control group.     

No association of endometriosis with glutathione S-transferase M1 and T1 null mutations in a Japanese population

OBJECTIVE: Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and with environmental factors to produce the phenotype. We investigated the frequency of glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) null mutations in women with endometriosis in a Japanese population. METHODS: One hundred fourteen unrelated women with endometriosis were enrolled. Samples of umbilical cord blood obtained from 179 female newborn infants were used as population controls. Genomic DNA isolated from endometriosis patients and controls were subjected to multiple polymerase chain reactions to determine the GSTM1 and GSTT1 genotypes. RESULTS: There were no significant differences in the frequencies of the GSTM1 (P = .83, odds ratio 0.95) and GSTT1 (P = .24, odds ratio 0.75) null mutations between endometriosis patients and controls. The endometriosis group was divided into a subgroup of stage IV disease only, but no statistically significant differences were observed in the frequency of the GSTM1 null mutation (P = .88, odds ratio 0.96, 95% confidence interval 0.57-1.63) and the GSTT1 null mutation (P = .33, odds ratio 0.77, 95% confidence interval 0.45-1.30) between any of these groups and the controls. CONCLUSION: These findings suggest that the GSTM1 and GSTT1 null mutations are not likely to be associated with an increased risk of endometriosis in a Japanese population.     

Glutathione S-transferase polymorphisms and ovarian cancer treatment and survival

OBJECTIVE: Members of the glutathione S-transferase (GST) family have been shown to have functional polymorphisms that may affect drug metabolism and influence the effects of chemotherapy and survival from cancer. GSTM1, GSTT1, and GSTP1 genotypes were evaluated for their role in ovarian cancer treatment and survival. METHODS: DNA was extracted from tumor tissues of 215 patients diagnosed with primary epithelial ovarian cancer. GSTM1 and GSTT1 genotypes were determined by multiplex PCR; GSTP1 genotypes were assessed with PCR-RFLP. Associations between GST polymorphisms and risk of ovarian cancer progression or death were analyzed using Cox proportional hazards regression; subgroups of patients receiving different chemotherapeutics were also evaluated. RESULTS: GST polymorphisms were not found to be associated with patient or tumor characteristics or response to treatment. However, GSTM1 null patients were less likely to have disease progression (HR: 0.65, 95% CI: 0.43-0.99) or to die (HR: 0.68, 95% CI: 0.45-1.03) compared to patients with GSTM1. Patients with GSTM1 null and GSTP1 ile/val or val/val (reduced function) had a further reduction in risk of disease progression compared to patients with GSTM1 or GSTP1 ile/ile (HR: 0.42, 95% CI: 0.24-0.75). A similar association was also suggested for overall survival (HR: 0.61, 95% CI: 0.36-1.05). Subgroup analyses indicated that the effects of GST on survival were more pronounced among patients treated with specific chemotherapeutics. CONCLUSION: These findings support the idea that reduced GST function may improve ovarian cancer survival after post-operative chemotherapy; evaluation of GST functional polymorphisms may help to predict ovarian cancer prognosis.     

Association of XRCC1 Arg399Gln and OGG1 Ser326Cys polymorphisms with the risk of cervical cancer in Japanese subjects

OBJECTIVE: In this study, genetic polymorphisms, XRCC1 Arg399Gln and OGG1 Ser326Cys were examined with reference to cervical cancer risk in a population-based incident case-control study in Japan. METHODS: The cases comprised 131 cervical cancer patients: 87 cases with squamous cell carcinoma (SCC) and 44 with adenocarcinoma (ADC) or adenosquamous carcinoma (ADSC). Controls were sampled from 320 healthy women who underwent a health checkup. RESULTS: The frequency of the XRCC1 399GlnGln genotype was higher in individuals with adenocarcinoma/adenosquamous carcinoma than in the healthy controls (OR = 2.98, 95% CI = 1.11-8.01, P = 0.030). However, no association was demonstrated in SCC. Analysis of OGG1 Ser326Cys polymorphism showed no significant differences between cervical cancer patients and controls. In stratification analysis, significant elevated risk of adenocarcinoma/adenosquamous carcinoma was associated with the XRCC1 399GlnGln genotype among nonsmokers (OR = 3.85, 95% CI = 1.28-11.59, P = 0.017), but not among smokers. No gene-gene interaction was observed in our case subjects. CONCLUSION: This is the first report that the XRCC1 Arg399Gln polymorphism might be important in relation to the risk of adenocarcinoma/adenosquamous carcinoma of the cervix.     

Human papillomavirus infection in the female population of Antwerp, Belgium: prevalence in healthy women, women with premalignant lesions and cervical cancer

Worldwide there is a strong relation between the presence of human papillomavirus (HPV) and the development of cervical cancer. This study investigated the prevalence and genotype of HPV in women with normal smears, women with premalignant lesions and women with cervical cancer in Antwerp, Belgium. Type-specific polymerase chain reaction (PCR) for HPV types 16 and 18 and general primer PCR (GP5+/6+) was performed on DNA extracted from paraffin-embedded tissue from women with lesions or fresh material from controls. HPV was detected in 11% of controls, 61% of women with atypia, 77% of women with CIN lesions and 88% of women with cervical carcinoma (chi2 trend, 273, p<0.001). The odds ratio for high-risk HPV types was 9.3 for atypia (95%CI. 4.3-19.8), 33.6 for CIN lesions (95%CI, 19.3-58.6) and 78.8 for cervical cancer (95%CI, 39.2-158.3). In total, 19 different HPV genotypes were detected, including five low risk HPV types. Seven of the 14 high-risk HPV types were detected in cervical cancer patients. Based on our study it is suggested that a prophylactic vaccine based on a cocktail of a limited number of high-risk HPV types should be considered in order to protect most women from developing cervical cancer.