Cervical Cancer In Indian Women Research Articles

Primary and secondary prevention of cervical cancer in Indian women using a public private participation approach: results of a pilot program

Primary and secondary prevention of cervical cancer in Indian women using a public private participation approach: results of a pilot program

Socio-demographic Characteristics and Use of Pap Smear for Cervical Cancer Screening Among Women of Eastern Part of India

Cervical cancer is the second most common cancer in India with high incidence and mortality rates. The aim of the study was to examine the association of risk with cervical cancer by Pap smear screening approach. This study design is based on retrospective data collection from case files of Cancer Detection Centre (CDC) who attended during the period of January 1995 to September 2016. The data were analysed using descriptive statistics, cross-tabulation and Pearson’s chi-square test. The study included 1195 women of whom 31.4% were aged 26–35 years; 91.2% Hindus; 80.3% housewives; 64.8% school educated; 85.8% married; 97.9% non-vegetarian; and 53.9% small family size. The above parameters were highly significant with the clinical diagnosis of cervical lesions by Pap test (p < 0.05). Addictions like betel leaf and smoking/chewing tobacco have shown significant correlation with cytological test (p < 0.05). Gynaecologic history including menarche, menstrual type, menopause, parity, abortion and mode of delivery had strong correlation with Pap test (p < 0.05). The chief complaints, clinical examination of cervix, clinical diagnosis and size of uterus had strong correlation with cytological findings (p = 0.001). The findings of the present study indicate that demographic characteristics, addictions, gynaecological and obstetric history and medical characteristics are strongly associated with increased risk of cervical cancer in Indian women. Furthermore, Pap smear is an effective screening method in low-cost infrastructure and for early detection.

E2F1 genetic variants and risk of cervical cancer in Indian women.

Altered expression of many E2F family members have been reported in various human cancers. In this study, we investigated the role of non-synonymous single nucleotide polymorphisms (rs3213172 C/T, rs3213173 C/T, and rs3213176 G/A) of the gene E2F1 with cervical cancer. A total of 181 samples including 90 cervical cancer patients and 91 healthy controls were genotyped. The genotype frequencies of these polymorphisms in collected samples were determined by either PCR-RFLP or PCR-ARFLP methods. SHEsis software was used to analyze the haplotypes. Statistically significant differences in the alleles and the genotypes frequencies were observed in rs3213172 (C/T) and rs3213173 (C/T) polymorphisms. The rs3213172 (C/T) polymorphism was a risk factor for cervical cancer in dominant model (odds ratio (OR) 1.96; 95% confidence interval (CI) 1.07, 3.60; P = 0.02) and heterozygous model (OR 1.90; 95% CI 1.01, 3.57; P = 0.04). The rs3213173 (C/T) polymorphism increased the risk of cervical cancer in the homozygous model (OR 2.71; 95% CI 1.11, 6.58; P = 0.02). The rs3213176 (G/A) polymorphism was not associated with cervical cancer risk in any of the genotypic models. In the haplotypes analysis, three haplotypes (CTG, TCG, and TTA) were associated with the cervical cancer risk. These findings revealed that rs3213172 (C/T) and rs3213173 (C/T) polymorphisms and haplotypes (CTG, TCG, and TTA) of the E2F1 gene might play role in the susceptibility of cervical cancer. This is the first report showing an association of these polymorphisms with the cervical cancer risk.

Meta-Analysis of Polymorphic Variants Conferring Genetic Risk to Cervical Cancer in Indian Women Supports CYP1A1 as an Important Associated Locus

Objective:Association of multiple polymorphic variants with cervical cancer has been elucidated by several candidate gene based as well as genome-wide association studies. However, contradictory outcomes of those studies have failed to estimate the true effect of the polymorphic variants on cervical cancer.Methods:Literature mining of the PubMed database was done to gather all the publications related to genetic association with cervical cancer in India. Out of 98 PubMed hits only 29 genetic association studies were selected for meta-analysis based on specific inclusion criteria. A fixed-effect meta-analysis was performed to evaluate the overall association of the genetic polymorphisms with cervical cancer. Cochran’s Q test was performed to assess between study heterogeneity. Publication bias was also estimated by funnel plots and Egger’s regression test. Further, sub-group analysis was conducted by fixed-effect meta-regression to assess the impact of polymorphisms on cervical cancer in the presence of Human Papilloma Virus (HPV).Result:Following a fixed-effect model, meta-analysis was conducted that revealed 2 polymorphic variants viz. ‘deletion polymorphism (Del2) (OR=1.79, 95% CI= 1.08-2.95, P=0.023) in GSTM1’ and ‘rs1048943 (OR = 2.34, 95% CI=1.37-3.99, P=0.0018) in CYP1A1’ to be associated with cervical cancer. However, multiple testing correction showed only rs1048943 of CYP1A1 to be significantly associated (P-value=0.029) with cervical cancer with significant publication bias (P-value=0.0113) as estimated by Egger’s regression test. The polymorphic variants ‘rs1801131’, ‘rs1801133’, ‘rs2430561’, ‘rs1799782’, ‘rs25486’ and ‘rs25487’ showed significant (p<0.05) evidence of heterogeneity between studies by Cochran’s Q test and also by heterogeneity index (I2) calculation.Conclusion:Therefore, our study revealed significant association of rs1048943 in CYP1A1, but a nominal association of deletion polymorphism (Del2) in GSTM1 with cervical cancer, which provides a comprehensive insight on the true effect of the polymorphisms, reported in various case-control studies, on the risk of the development of cervical cancer in Indian women.

Higher Prevalence of Human Papillomavirus Infection in Adolescent and Young Adult Girls Belonging to Different Indian Tribes with Varied Socio-Sexual Lifestyle

BackgroundDespite high prevalence of human papillomavirus (HPV) infection and cervical cancer in Indian women, no study has been done in tribal populations whose socio-sexual lifestyle is different. Therefore, HPV screening has been carried out in pre-adolescent, adolescent and young adult tribal girls using self-collected urine samples.Methods20–35 ml self-collected midstream urine samples were obtained from a total of 2278 healthy tribal girls (9–25 years) comprising pre-adolescent, adolescent and young adults from three Indian states: Madhya Pradesh, Jharkhand and Chhattisgarh. β-globin positive 2034 samples were employed for HPV detection and genotyping.ResultsThe overall prevalence of HPV infection in tribal girls was 12.9% (262/2034). More than 65% (172/262) of them were infected with HR-HPV types of which HPV16 was the most predominant type (54%). Young adult girls aged 18–25 years showed a significantly higher prevalence of HPV infection (19.2%; OR = 3.36; 95% CI 2.97–6.34, P<0.001) as compared to that in adolescent (11.4%; OR = 1.82; 95% CI 1.20–2.76, P<0.01) or pre-adolescent girls (6.6%).ConclusionThis is a first study showing significantly a very high prevalence of HPV infection in adolescent and young adult tribal girls possibly due to different socio-sexual behavior, indicating a serious health concern for Indian tribal women.

Cervical cancer in Indian women reveals contrasting association among common sub-family of HLA class I alleles.

We studied the relationship between human leukocyte antigen (HLA) class I alleles and cervical cancer among Indian women. Seventy-five cervical cancer cases were compared with 175 noncancer controls. Cervical biopsy tissue specimen from cancer cases and cervical swab specimen from controls were collected for HPV detection and typing. Blood was taken for HLA typing by PCR-SSOP method. The impact of HLA class I alleles on cervical cancer risk was evaluated using StatCalc program (Epi Info version 6.0.4. CDC Atlanta, GA, USA), and confirmed with Bonferroni correction. Results revealed HLA-B*37, HLA-B*58 were associated significantly with increased risk while HLA-B*40 with decreased risk for cervical cancer. At high-resolution analysis after Bonferroni correction, HLA-B*37:01 allele was associated with increased risk, whereas HLA-B*40:06 was with decreased risk for cervical cancer. HLA-B*37:01 and HLA-B*40:06 belong to the same superfamily of HLA-B44. In silico analysis revealed different binding affinities of HLA-B*37:01 and HLA-B*40:06 for the epitopes predicted for E6 and L1 proteins of HPV16. The higher binding affinity of epitopes to B*40:06, as revealed by docking studies, supports the hypothesis that this allele is able to present the antigenic peptides more efficiently than B*37:01 and thereby can protect the carriers from the risk of cervical cancer. Thus, there is a clear indication that HLA plays an important role in the development of cervical cancer in HPV-infected women. Identification of these factors in high-risk HPV-infected women may help in reducing the cervical cancer burden in India.

CTLA-4 gene polymorphism at position +49 A>G in exon 1: a risk factor for cervical cancer in Indian women

Single nucleotide polymorphisms (SNPs) in the CTLA-4 gene exert differential effects on T-cell response to viral infection. We aimed to evaluate the association of two SNPs of the CTLA-4 gene with cervical cancer in Indian women. The two polymorphic loci, one in the promoter region -318 C>T, rs5742909 (100 cervical cancer cases and 101 controls) and the other in exon 1 +49 A>G, rs231775 (104 cervical cancer cases and 162 controls) were genotyped using polymerase chain reaction-restriction fragment length polymorphism methods. Haplotype block structure was determined using Haploview 4.2. The statistical analyses were performed using a commercially available statistical software package, whereas PyPop was used to calculate the haplotypic frequencies. In this case-control study, the A/A genotype frequency (30.76% vs. 17.6%, P = 0.01) as well as the allelic frequency for A (52.8% vs. 43.5%, P = 0.04) was significantly higher in cases compared to controls. No significant association was seen in the -318 C>T polymorphism. In forward stepwise binary logistic regression analysis considering age and parity as potential confounders, significant association was demonstrated between +49 A/A and cervical cancer. Most likely, this is the first study from India to highlight the significant association between the CTLA-4 gene +49 A/A SNP and cervical cancer, thus adding to the global knowledge of the association of this SNP with cervical cancer.

Novel missense mutation in FHIT gene: interpreting the effect in HPV-mediated cervical cancer in Indian women

Human papillomavirus (HPV) is considered to be a major etiological factor but is not sufficient for the development of cervical cancer. Other host factors including altered tumor suppressor gene activities might contribute to the carcinogenic process. Fragile Histidine Triad (FHIT) has been shown to play a pivotal role in carcinogenesis. Therefore, we made an attempt to find out point mutation of FHIT gene in HPV mediated cervical cancer in Indian women. 112 cases of cervical carcinoma tissue biopsies and 38 cervical scrapes samples of normal cytology were employed for this study. Herein, we report a novel mutation identified at nucleotide position 655, at codon 98 from CAT --> CGT with ultimate replacement of amino acid Histidine by Arginine in cervical cancer cases. Molecular modeling was performed to predict the effect of this mutation in disease pathology. We predict that this change, His to Arg substitution in substrate-binding domain may generate catalytically inactive protein with loss of tumor suppressor activity.

Association between human leukocyte antigen class II alleles and human papillomavirus-mediated cervical cancer in Indian women

We investigated the association of human leukocyte antigen (HLA) II (DRB1 and DQB1) alleles with susceptibility to human papillomavirus (HPV)-associated cervical precancer and cancer cases in a hospital-based case–control study in a northern Indian population. A total of 202 subjects, including 100 patients comprising 31 cervical precancer (cervical intraepithelial neoplasia [CIN] 2/3) and 69 invasive cervical cancer cases, and 102 healthy controls participated in the study. Both patients and controls were screened for HPV infection using a polymerase chain reaction (PCR-based approach. Low-resolution PCR–sequence specific priming (PCR-SSP) was used to genotype HLA II (DRB1 and DQB1). Our results demonstrate that the DRB1*15 allele/DRB1*15-DQB1*06 haplotype may have a predisposition for HPV infection ( p c < 0.05) or cervical cancer/precancer ( p c < 0.05) development, whereas the DRB1*04 allele/DRB1*04-DQB1*03 haplotype might exhibit susceptibility to cervical precancerous lesions ( p c < 0.05). The DRB1*13 allele/DRB1*13-DQB1*06 haplotype was strongly protective against risk to HPV infection ( p c < 0.002) as well as cervical cancer ( p c 0.01). Therefore, we have demonstrated that HLA DR-DQ polymorphisms are involved in genetic susceptibility to cervical cancer or HPV infection in a northern Indian population.

Effect of aberrant promoter methylation of FHIT and RASSF1A genes on susceptibility to cervical cancer in a North Indian population

As current evidence suggests the involvement of epigenetic modification of tumour suppressor genes in human cancer, we investigated the aberrant promoter methylation of FHIT and RASSF1A genes in human papillomavirus (HPV)-mediated cervical cancer in Indian women. We analysed 60 cervical cancer tissue biopsies of different clinical stage and histological grading and 23 healthy control samples with normal cervical cytology. Methylation-specific polymerase chain reaction (MSP) was performed to analyse the methylation status of FHIT and RASSF1A genes and confirmed by sequencing. Both patients and controls were screened for HPV infection and 98% of the HPV-infected cases showed positivity for HPV type 16. Aberrant promoter methylation of the FHIT gene was found in 28.3% (17/60) of cases and of the RASSF1A gene in 35.0% (21/60) of cases; promoter methylation of both the genes was found in 13.3% (8/60) of cervical cancer cases. Methylation was significantly (p<0.01) associated with the cervical cancer cases compared with controls. None of the 23 controls was found to be methylated in either of these genes. This is the first study indicating a correlation between the promoter methylation of FHIT and RASSF1A genes and the clinical stage and histological grading of cervical carcinoma in Indian women. Future studies are underway to examine the practical implications of these findings for use as a biomarker.

Allelic Variations in 5, 10-Methylenetetrahydrofolate Reductase Gene and Susceptibility to Cervical Cancer in Indian Women

Methylenetetrahydrofolate reductase (MTHFR) gene located on chromosome 1p36.3 catalyses the conversion of 5,10-methylenetetrahydrofolate to 5,methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms in the MTHFR gene have been identified, 677C>T in exon 4, leading to substitution of alanine by valine and 1298A>C in exon 7 which leads to the replacement of glutamic acid by alanine resulting into reduced enzyme activity. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair makes MTHFR an attractive candidate for cancer predisposing gene. In order to elucidate the role of MTHFR polymorphism in cervical cancer, both the exons for 677C>T and 1298A>C mutations were analyzed among 219 females, including 77 females with normal cervical cytology, 80 with cervical dysplasia and 62 with squamous cell carcinoma of uterine cervix. Females with mutant allele at 677 position (CT/TT genotypes) were found to be almost three times the risk of cervical dysplasia than females with CC genotype [OR, 2.9; (CI, 1.5-5.7)], but were less likely to develop squamous cell carcinoma [OR, 1.5 (CI, 0.7-3.2)]. Similar findings were observed for mutation at 1298 position, females with AC/CC genotypes were almost four times the risk of cervical dysplasia [OR, 4.3 (CI, 2.1-9.0)], as compared to AA genotype. Our study lends further support to the hypothesis that the MTHFR polymorphism (677C>T or 1298A>C) is involved in susceptibility to cervical dysplasia.

TNFα–308G/A Polymorphism as a Risk Factor for HPV Associated Cervical Cancer in Indian Population

Background: Investigation of the potential association of single nucleotide polymorphisms (SNPs) at –308 G/A and –238 G/A of Tumor necrosis factor α (TNFα) with susceptibility to HPV-16 associated cervical cancer in Indian women. Methods: The study included 165 histologically confirmed cases with 45 precancer and 120 cancer patients and an equal number (165) of healthy controls with normal cervical cytology. PCR-RFLP was employed to analyze TNFα promoter polymorphisms, which were confirmed by direct sequencing. Both patients and controls were screened for Human Papillomavirus (HPV) infection. Results: The frequency of –308 A allele in TNFα was significantly higher in cases compared with control subjects (21% in cases vs. 9% in controls; p < 0.01), with an odds ratio of 2.7 (95% CI = 1.41–5.15). Also, women carrying A allele for this locus presented 3 times increased susceptibility to HPV 16 infection as evident from carrier genotype distribution between HPV positive cases and control subjects (24% in HPV positive cases vs. 9% in controls; p < 0.01; OR = 3.1; 95% CI = 1.60–6.03). No such association was found for TNFα–238 (G/A) polymorphism with the risk of development of cervical cancer. Conclusion: It suggests that SNP at –308 (G/A) of TNFα promoter may represent an increased risk for HPV infection and development of cervical cancer in Indian women.

HLA B*1301 and B*1801 Alleles are Positively Associated with HPV Related Cervical Cancer in Women from Kolkata, Eastern India

The incidence of cervical cancer is high in Indian women. Human papillomavirus (HPV) infection is known to be the major risk factor for cervical cancer. Further both viral and host genetic factors have been postulated as important determinants. In the present study 31 suspected Indian women were analyzed molecularly for their HPV infection status, cervical cancer and HLA A, B and Cw allele associations. Among the 13 HPV-16 positive women the HLA analysis revealed a positive association for B*1301 and B*1801 alleles and a negative association with B*4006 in the six cervical cancer patients compared with seven histopathologically normal controls. Our study is the first report towards HPV related cervical cancer in Indian women which suggests that HPV type and HLA allele associations are population dependent.

HPV16 E2 gene disruption and polymorphisms of E2 and LCR: Some significant associations with cervical cancer in Indian women

Objectives. We evaluated the status of the HPV16 E2 gene (disrupted or intact), nucleotide sequence alterations within intact E2 genes and LCR of HPV16 isolates in a group of CaCx cases (invasive squamous cell carcinomas, n = 81) and population controls (normal cervical scrapes, n = 27) from Indian women. Methods. E2 disruption was detected by amplifying the entire E2 gene with single set of primers, while overlapping primers were used to determine if any particular region got selectively disrupted. Nucleotide variations in E2 and LCR were analyzed by PCR amplification followed by bi-directional sequencing. The associations between the viral factors and CaCx were analyzed using Fisher's Exact or Chi-squared test and interpreted as OR (95% CI) and P values. Results. E2 disruption was significantly higher among the cases [3.38 (1.07–10.72); P = 0.02], which was maximum in the region between nucleotides 3650 and 3872 (DNA-binding region). The European (E) variant was found to be the prevalent subgroup (87.76% among cases and 96.30% among the controls), and the remaining samples were Asian-American variants. Among the E subgroup, variation at position 7450 (T > C) within the E2-binding site-IV was found to be significantly higher among the E2 undisrupted cases (21/37; 56.76%), compared to controls (5/18; 27.78%) [3.41 (1.01–11.55); P = 0.03]. Conclusions. Besides HPV16 E2 disruption, LCR 7450T > C variation within undisrupted E2 of E subgroup appears to be a major factor contributing to the risk of CaCx development in Indian women. Furthermore, polymorphisms in the E2 gene of HPV16 may not be significant for disease risk.

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.

HLA DQB1*03 Genotypes and Susceptibility to Cervical Cancer in Indian Women

KEYWORDS Cervical cancer; human papillomavirus; HLA DQB1*03 genotypes; age of subjects ABSTRACT DNA from i) fresh tissues derived out of 89 women with CaCx (61 HPV16/18 positive) and ii) cervical scrapes from 213 cytologically normal women (73 HPV16/18 positive) were genotyped for HLA DQB1*03 by PCR and RFLP. The distribution of the genotypes of HLA DQB1*03 differed significantly between the malignant and control subjects (p= 0.022). The homozygous genotype was overrepresented among those having CaCx (ORage- adjusted=2.94, 95% CI= 1.49-5.81, p=0.002), or HPV16/18 positive CaCx (ORage-adjusted =2.32, 95% CI= 1.07-5.01; p=0.033), when this was compared to the other genotypes (HLADQB1*03 non-homozygous, i.e. heterozygous and null together). Analysis restricted to the HPV16/18 positive CaCx and cytologically normal subjects failed to show such association. The heterozygous genotype, instead, showed a negative association with HPV16/18 positive CaCx over the null genotype (ORage-adjusted =0.42, 95% CI= 0.18-0.96; p=0.040) when HPV16/18 positive CaCx cases were compared with HPV negative cytologically normal controls. The association of HLA DQB1*03 homozygosity with CaCx was noted among those of age < 47 years. The genotypes of HLA DQB1*03 are likely to be important in determining the susceptibility to HPV or HPV16/18 related CaCx in Indian women.

HLA DQB1*03 Genotypes and Susceptibility to Cervical Cancer in Indian Women

HLA DQB1*03 Genotypes and Susceptibility to Cervical Cancer in Indian Women

Double jeopardy: HIV and cervical cancer in Indian women

Double jeopardy: HIV and cervical cancer in Indian women

Double jeopardy: HIV and cervical cancer in Indian women

Double jeopardy: HIV and cervical cancer in Indian women

P53 codon 72 polymorphism and susceptibility to development of human papilloma virus-associated cervical cancer in Indian women.

Infection with human papilloma virus (HPV) is an important etiological factor in the development of cervical cancer and it has been proposed that individuals homozygous for Arg/Arg at codon-72 of p53 are seven times more susceptible to HPV-mediated cancer. In this study, we have analyzed the genetic predisposition of the India population to HPV infection and cervical carcinogenesis. We investigated 71 cases of squamous cell carcinoma of the cervix, 14 cases of low-grade squamous intraepithelial lesions, 25 cases of high-grade squamous intraepithelial lesions and 29 noncancer controls for presence of HPV16/18 infections by L-1-specific PCR assay and Southern hybridization, and its association with polymorphism at p53 codon 72. We observed that 69.1% (76/110) of the cervical cancer patients were HPV positive, among which the presence of HPV16, 18 and 16/18 coinfection was 40.9%, 8.2% and 13.6%, respectively. The allele frequencies of the three p53 genotypes Arg/Arg, Arg/Pro and Pro/Pro in the HPV-positive tumour samples were 0.34, 0.57 and 0.09 in comparison with frequencies of 0.18, 0.44 and 0.38 for HPV-negative tumours. Hence, there is a significant difference in the allelic frequency of p53 Arg/Arg in high-risk HPV-infected cervical carcinoma cases (0.34) and HPV-negative carcinomas (0.18). Our results indicate a striking over-representation of homozygous arginine at codon 72 of p53 in HPV-associated cervical carcinogenesis. We conclude that women with Arg/Arg homozygous allele are more prone to infection by HPV16/18, which leads to cervical carcinomas having poor prognosis.