Anita Koushik

p53 Codon 72 Polymorphism and Cervical Neoplasia A Meta-Analysis Review

The Arg/Arg genotype versus Arg/Pro or Pro/Pro at codon 72 of the p53 gene has been implicated as a risk marker in cervical neoplasia. However, research on this topic has produced controversial results. We reviewed the published literature to summarize the association and to identify methodological features that may have contributed to the heterogeneity. Information on specific methodological features of studies addressing this topic published between 1998 and 2002 were obtained. Study-specific odds ratios (ORs) were combined in a meta-analysis, assuming random effects. To identify characteristics that significantly contributed to heterogeneity, we used meta-regression analysis. We identified 50 articles, of which 45 were included in the meta-analyses and regressions. No evidence of association or heterogeneity was detected for preinvasive lesions. For invasive cervical cancer with undefined histology, the Arg/Arg genotype was not found to affect risk (OR, 1.1; 95% confidence interval (CI), 0.9–1.3). However, a slightly increased risk was observed for squamous cell carcinoma (OR, 1.5; 95% CI, 1.2–1.9) and adenocarcinoma (OR, 1.7; 95% CI, 1.0–2.7). Meta-regression analysis identified that the most important factor contributing to heterogeneity among results for invasive lesions was departures from Hardy-Weinberg equilibrium in the control group. Summary ORs for studies in equilibrium were essentially null. A possible susceptibility role by the p53 codon 72 polymorphism at a late carcinogenetic stage in cervical cancer cannot be ruled out. However, various methodological features can contribute to departures from Hardy-Weinberg equilibrium and consequently to less than ideal circumstances for the examination of this polymorphism. Future investigations require appropriate attention to design and methodological issues.

Dairy Products and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies

Background: Dairy foods and their constituents (lactose and calcium) have been hypothesized to promote ovarian carcinogenesis. Although case-control studies have reported conflicting results for dairy foods and lactose, several cohort studies have shown positive associations between skim milk, lactose, and ovarian cancer. Methods: A pooled analysis of the primary data from 12 prospective cohort studies was conducted. The study population consisted of 553,217 women among whom 2,132 epithelial ovarian cases were identified. Study-specific relative risks and 95% confidence intervals were calculated by Cox proportional hazards models and then pooled by a random-effects model. Results: No statistically significant associations were observed between intakes of milk, cheese, yogurt, ice cream, and dietary and total calcium intake and risk of ovarian cancer. Higher lactose intakes comparing ≥30 versus <10 g/d were associated with a statistically significant higher risk of ovarian cancer, although the trend was not statistically significant (pooled multivariate relative risk, 1.19; 95% confidence interval, 1.01-1.40; Ptrend = 0.19). Associations for endometrioid, mucinous, and serous ovarian cancer were similar to the overall findings. Discussion: Overall, no associations were observed for intakes of specific dairy foods or calcium and ovarian cancer risk. A modest elevation in the risk of ovarian cancer was seen for lactose intake at the level that was equivalent to three or more servings of milk per day. Because a new dietary guideline recommends two to three servings of dairy products per day, the relation between dairy product consumption and ovarian cancer risk at these consumption levels deserves further examination. (Cancer Epidemiol Biomarkers Prev 2006;15(2):364–72)

p53 Arg72Pro polymorphism and risk of colorectal adenoma and cancer

A single nucleotide polymorphism (SNP) at codon 72 of the p53 gene (Arg72Pro) alters the p53 protein structure and affects its activity. We investigated this SNP in relation to colorectal adenoma and cancer among men and women from case–control studies nested within the Nurses Health Study, the Health Professionals Follow‐up Study and the Physicians Health Study. Among 856 colorectal adenoma cases and 1,184 controls, we observed a modest association with p53 Arg72Pro genotype (multivariate odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.04–1.50 for Arg/Pro and Pro/Pro vs. Arg/Arg). This association did not vary by colorectal site or by sex. Among 442 colorectal cancer cases and 904 controls, we observed no significant overall association between p53 Arg72Pro genotype and colorectal cancer (multivariate OR = 1.14, 95% CI = 0.90–1.45). However, when colorectal site and sex was accounted for, the Pro carrier genotypes compared to Arg/Arg were associated with an increased risk of proximal colon cancers in women (multivariate OR = 2.59, 95% CI = 1.49–4.52) though not with distal colon or rectal cancers, while among men the same genotypes were associated with an increased risk of distal colon cancers (multivariate OR = 2.09, 95% CI = 1.28–3.40) but not proximal colon or rectal cancers. Our results suggest that Arg72Pro may play a role in the early stages of colorectal neoplasia and possibly in progression to invasive disease, depending on site and sex.

Fruits and Vegetables and Ovarian Cancer Risk in a Pooled Analysis of 12 Cohort Studies

Because fruits and vegetables are rich in bioactive compounds with potential cancer-preventive actions, increased consumption may reduce the risk of ovarian cancer. Evidence on the association between fruit and vegetable intake and ovarian cancer risk has not been consistent. We analyzed and pooled the primary data from 12 prospective studies in North America and Europe. Fruit and vegetable intake was measured at baseline in each study using a validated food-frequency questionnaire. To summarize the association between fruit and vegetable intake and ovarian cancer, study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Among 560,441 women, 2,130 cases of invasive epithelial ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. Total fruit intake was not associated with ovarian cancer risk—the pooled multivariate RR for the highest versus the lowest quartile of intake was 1.06 [95% confidence interval (95% CI), 0.92-1.21; P value, test for trend = 0.73; P value, test for between-studies heterogeneity = 0.74]. Similarly, results for total vegetable intake indicated no significant association (pooled multivariate RR, 0.90; 95% CI, 0.78-1.04, for the highest versus the lowest quartile; P value, test for trend = 0.06; P value, test for between-studies heterogeneity = 0.31). Intakes of botanically defined fruit and vegetable groups and individual fruits and vegetables were also not associated with ovarian cancer risk. Associations for total fruits and vegetables were similar for different histologic types. These results suggest that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer.

Distribution of human papillomavirus genotypes in cervical intraepithelial neoplasia and invasive cervical cancer in Canada

Infection with high‐risk human papillomavirus (HPV) causes cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC). The distribution of HPV types in cervical diseases has been previously described in small studies for Canadian women. The prevalence of 36 HPV genotypes in 873 women with CIN and 252 women with ICC was assessed on cervical exfoliated cells analyzed with the Linear Array (Roche Molecular System). HPV16 was the most common genotype in CIN and ICC. The seven most frequent genotypes in order of decreasing frequency were HPV16, 51, 52, 31, 39, 18, and 56 in women with CIN1, HPV16, 52, 31, 18, 51, 39, and 33 in women with CIN2, HPV16, 31, 18, 52, 39, 33, and 58 in women with CIN3, and HPV16, 18, 45, 33, 31, 39, and 53 in women with ICC. HPV18 was detected more frequently in adenocarcinoma than squamous cell carcinoma (Pu2009=u20090.013). Adjustment for multiple type infections resulted in a lower percentage attribution in CIN of HPV types other than 16 or 18. The proportion of samples containing at least one oncogenic type was greater in CIN2 (98.4%) or CIN3 (100%) than in CIN1 (80.1%; Pu2009<u20090.001 for each comparison). Multiple type infections were demonstrated in 51 (20.2%) of 252 ICC in contrast to 146 (61.3%) of 238 women with CIN3 (Pu2009<u20090.001). Adjusting for multiple HPV types, HPV16 accounted for 52.1% and HPV18 for 18.1% of ICCs, for a total of 70.2%. Current HPV vaccines should protect against HPV types responsible for 70% of ICCs in Canadian women. J. Med. Virol. 83:1034–1041, 2011.

Selected class I and class II HLA alleles and haplotypes and risk of high-grade cervical intraepithelial neoplasia

Human leukocyte antigens (HLAs) present foreign antigens to the immune system and may be important determinants of cervical neoplasia. Previously published associations between HLA and cervical neoplasia exhibit considerable variation in findings. The biomarkers of cervical cancer risk (BCCR) case‐control study addressed the role of specific HLA alleles as cofactors in the development of high‐grade cervical intraepithelial neoplasia (HG‐CIN) based on the most consistent evidence from published literature. Cases (N = 381) were women with histologically‐confirmed HG‐CIN attending colposcopy clinics and controls (N = 884) were women from outpatient clinics with normal cytological screening smears. Subjects were mainly of French‐Canadian descent. Cervical specimens were tested for human papillomavirus (HPV) DNA and HLA genotypes by PGMY L1 consensus primer PCR and a PCR sequence‐specific primer method, respectively. Unlike other studies, the DQB1*03 and DRB1*13 allele groups were not associated with risk of HG‐CIN. The B7‐DRB1*1501‐DQB1*0602 haplotype was associated with a 41% overall reduction in HG‐CIN risk (odds ratio [OR] = 0.59; 95% confidence interval [CI]: 0.36–0.96), and an 83% reduction in risk of HG‐CIN among HPV 16 or HPV 18‐positive subjects (OR = 0.17; 95%CI: 0.05–0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR = 8.44, 95%CI: 1.12–63.73). In conclusion, the B7‐DRB1*1501‐DQB1*0602 haplotype was protective against HG‐CIN, especially in individuals infected with oncogenic HPV, but the mechanism of the association seems to involve multiple steps in the natural history of HPV and CIN.

Human Papillomavirus Type 33 Polymorphisms and High-Grade Squamous Intraepithelial Lesions of the Uterine Cervix

BACKGROUNDnWe investigated the association between polymorphisms of human papillomavirus (HPV)-33 and squamous intraepithelial lesions (SILs).nnnMETHODSnEndocervical specimens from 89 women infected with HPV-33, out of a total of 5347 recruited for 2 case-control and 2 cohort studies, were further analyzed by polymerase chain reaction sequencing of the long control region (LCR), E6, and E7.nnnRESULTSnOf the 89 samples, 64 were normal, 7 had low-grade SILs (including 3 determined by histopathologic analysis), 15 had high-grade SILs (HSILs, including 14 determined by histopathologic analysis), and 3 had an unknown diagnosis. Non-prototype-like LCR variants were significantly associated with HSILs (age- and study site-adjusted odds ratio [OR], 9.2 [95% confidence interval {CI}, 1.8-45.9]). The C7732G variation, which results in the loss of a putative binding site for the cellular upstream stimulatory factor, was associated with HSILs (age- and site-adjusted OR, 8.0 [95% CI, 1.5-42.8]). E6 and E7 polymorphisms were not associated with HSILs. Samples collected at 6-month intervals from 14 participants contained the same variant. The HPV-33 MT 1-0-0 variant carrying the G7584A variation was detected more frequently in women from Brazil (7/20 [35%]) than in women from Canada (1/65 [1.5%]; P=.001).nnnCONCLUSIONnIntratypic LCR variants of HPV-33 seem to vary geographically and to differ with respect to their oncogenic potential.

Intake of the major carotenoids and the risk of epithelial ovarian cancer in a pooled analysis of 10 cohort studies

Carotenoids, found in fruits and vegetables, have the potential to protect against cancer because of their properties, including their functions as precursors to vitamin A and as antioxidants. We examined the associations between intakes of α‐carotene, β‐carotene, β‐cryptoxanthin, lutein/zeaxanthin and lycopene and the risk of invasive epithelial ovarian cancer. The primary data from 10 prospective cohort studies in North America and Europe were analyzed and then pooled. Carotenoid intakes were estimated from a validated food frequency questionnaire administered at baseline in each study. Study‐specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random‐effects model. Among 521,911 women, 2,012 cases of ovarian cancer occurred during a follow‐up of 7–22 years across studies. The major carotenoids were not significantly associated with the risk of ovarian cancer. The pooled multivariate RRs (95% confidence intervals) were 1.00 (0.95–1.05) for a 600 μg/day increase in α‐carotene intake, 0.96 (0.93–1.03) for a 2,500 μg/day increase in β‐carotene intake, 0.99 (0.97–1.02) for a 100 μg/day increase in β‐cryptoxanthin intake, 0.98 (0.94–1.03) for a 2,500 μg/day increase in lutein/zeaxanthin intake and 1.01 (0.97–1.05) for a 4,000 μg/day increase in lycopene intake. These associations did not appreciably differ by study (p‐values, tests for between‐studies heterogeneity >0.17). Also, the observed associations did not vary substantially by subgroups of the population or by histological type of ovarian cancer. These results suggest that consumption of the major carotenoids during adulthood does not play a major role in the incidence of ovarian cancer.

Risk factors for diabetic retinopathy in the Cree of James Bay

background The purpose of this project was to evaluate risk factors for diabetic retinopathy in the Cree population of James Bay, Ontario. methods A retrospective cohort design was employed. The cohort was made up of all known individuals who had previously been diagnosed with diabetes in the communities of Moose Factory and Moosonee, Ontario. Hypertension, body-mass index, serum lipid levels, renal function status, and hemoglobin A1C were the main exposures of interest. Values for these variables were determined from a retrospective chart review and were sought for each individual for a five-year interval beginning one year following the diagnosis of diabetes. Relative risks for the association of these variables with diabetic retinopathy were determined through both univariate and multivariate Poisson regression. The main outcome of interest in this study was the presence or absence of any diabetic retinopathy in either eye, as determined by a retinal specialist. results Significant univariate risks for the development of retinopathy included duration of diabetes, body-mass index, hemoglobin A1C, fasting blood glucose, insulin treatment, and serum cholesterol levels. In multivariate analyses, predictors of diabetic retinopathy included body-mass index, insulin treatment, and serum cholesterol levels. An increase in body-mass index reduced the risk of diabetic retinopathy (Relative Risk [RR] 0.64 per five kg/m 2 , 95% Confidence Interval [CI] 0.04 to 1.00). Insulin therapy was associated with an increased risk of retinopathy when compared to individuals on dietary therapy alone (Relative Risk [RR] 4.71, 95% Confidence Interval [CI] 1.16 to 19.16). For individuals with serum cholesterol levels above the average for the cohort, 5.2 mmol/L, the risk of retinopathy was increased (Relative Risk [RR] 2.38, 95% Confidence Interval [CI] 0.98 to 5.79). interpretation Elevated serum cholesterol, lower body-mass index and insulin treatment were all associated with an increased risk of diabetic retinopathy in the Cree of James Bay, Ontario.

Influence of human papillomavirus type 16 (HPV-16) E2 polymorphism on quantification of HPV-16 episomal and integrated DNA in cervicovaginal lavages from women with cervical intraepithelial neoplasia

Integrated human papillomavirus type 16 (HPV-16) viral loads are currently estimated by quantification with real-time PCR of HPV-16 E6 (RT-E6 and HPV-16 PG) and E2 (RT-E2-1) DNA. We assessed the influence of HPV-16 E2 polymorphism on quantification of integrated HPV-16 DNA in anogenital specimens. HPV-16 E2 was sequenced from 135 isolates (123 from European and 12 from non-European lineages). An assay targeting conserved HPV-16 E2 sequences (RT-E2-2) was optimized and applied with RT-E6 and RT-E2-1 on 139 HPV-16-positive cervicovaginal lavages collected from 74 women [58 human immunodeficiency virus (HIV)-seropositive and 16 HIV-seronegative]. Ratios of HPV-16 copies measured with RT-E2-2 and RT-E2-1 obtained with African 2 (median=3.23, range=1.92-3.49) or Asian-American (median=3.78, range=1.47-37) isolates were greater than those obtained with European isolates (median=1.02, range=0.64-1.80; P<0.02 for each comparison). The distribution of HPV-16 E2 copies measured in 139 samples with RT-E2-2 (median=6150) and RT-E2-1 (median=8960) were different (P<0.0001). The risk of high-grade cervical intraepithelial neoplasia (CIN-2,3) compared with women without CIN was increased with higher HPV-16 total [odds ratio (OR)=2.17, 95 % confidence interval (CI)=1.11-4.23], episomal (OR=2.14, 95 % CI=1.09-4.19), but not for HPV-16 integrated viral load (OR=1.71, 95 % CI=0.90-3.26), after controlling for age, race, CD4 count, HIV and HPV-16 polymorphism. The proportion of samples with an E6/E2 ratio >2 in women without squamous intraepithelial lesion (7 of 35) was similar to that of women with CIN-2,3 (5 of 11, P=0.24) or CIN-1 (5 of 14, P=0.50). HPV-16 E2 polymorphism was a significant factor that influenced measures of HPV-16 integrated viral load.