Person:

Cramer, Daniel

Introduction: Experimental studies suggest vitamin D inhibits ovarian carcinogenesis. Yet, epidemiologic studies of ovarian cancer risk and lifestyle correlates of vitamin D status, plasma 25-hydroxyvitamin D [25(OH)D], or vitamin D receptor (VDR) variants have been inconsistent. Objective: To evaluate VDR genetic associations by high vs. low predicted 25(OH)D, scores derived from known determinants of plasma 25(OH)D. To assess ovarian cancer associations with variants identified in genome-wide association studies (GWAS) of plasma 25(OH)D. Methods: We genotyped up to seven VDR and eight 25(OH)D GWAS variants in the Nurses’ Health Studies (562 cases, 1,553 controls) and New England Case–Control study (1,821 cases, 1,870 controls). We estimated haplotype scores using expectation-maximization-based algorithms. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI). We combined study results using DerSimonian and Laird meta-analysis. Results: Ovarian cancer risk increased per A allele of rs7975232 (VDR; OR = 1.12, 95% CI = 1.01–1.25) among all women. When stratified by predicted 25(OH)D, ovarian cancer was associated with rs731236 (VDR; per C allele OR = 1.31) and rs7975232 (OR = 1.38) among women with high predicted 25(OH)D, but not among women with low levels (P ≤ 0.009). We also observed heterogeneity by predicted 25(OH)D for the ovarian cancer association with VDR 3′ end haplotypes (P = 0.009). Of 25(OH)D-associated GWAS loci, rs7041 was associated with reduced ovarian cancer risk (per T allele OR = 0.92, 95% CI = 0.85-0.99), which did not differ by predicted 25(OH)D status. Conclusion: Our study suggests an influence of VDR 3′ end variants on ovarian cancer risk may be observed in women with high predicted 25(OH)D, which remained even after taking multiple comparisons into consideration. Future studies are needed to confirm our results and explore further the relation between vitamin D exposure, genetic variants, and ovarian cancer risk.

Objective

To investigate whether Galactose-1-phosphate uridyl transferase (GALT) variant genotypes were associated with epithelial ovarian cancer risk and to determine if this association was modified by lactose intake.

Design

two prospective cohort studies and a case-control study.

Setting

Academic institution.

Patient(s)

992 cases and 1050 population-based controls from a New England case-control study and 240 cases and 900 controls from the Nurses’ Health Studies.

Intervention(s)

None.

Main Outcome Measure(s)

Genotyping of the N314D variant and the 4-bp deletion (-119delGTCA) of GALT using the Taqman 5′ nuclease assay. Duarte1 (D1) genotype individuals have a missense mutation (N314D) associated with normal GALT activity unless it occurs together with an associated 4-bp deletion leading to reduced GALT activity (Duarte2 or D2).

Result(s)

Logistic regression analysis identified no association between D1/D2 genotypes and ovarian cancer risk (pooled RR, 1.1 (95% CI, 0.8–1.5) for D1 and 1.0 (95% CI, 0.7–1.4) for D2). We did not observe a significant interaction between D1 and D2 genotypes in analyses stratified by level of lactose intake (Pinteraction ≥ 0.3).

Conclusion(s)

D1 and D2 genotypes do not appear to play a role in the association between galactose intake, possible ovarian dysfunction and the link with ovarian cancer.

Inconsistent results for the role of dairy food intake in relation to ovarian cancer risk may reflect the potential adverse effects of lactose, which has been hypothesized to increase gonadotropin levels, and the beneficial anti-proliferative effects of calcium and vitamin D. Using data from the New England case-control study (1909 cases; 1989 controls) we examined dairy foods and nutrients in relation to risk of ovarian cancer overall, histological subtypes, and rapidly fatal versus less aggressive disease. We used logistic regression and polytomous logistic regression to estimate odds ratios and 95% confidence intervals. In models that were simultaneously adjusted for total (dietary plus supplements) calcium, total vitamin D and lactose, we observed a decreased overall risk of ovarian cancer with high intake of total calcium (Quartile 4 (Q4, >1319 mg/day) vs. Quartile 1 (Q1, <655 mg/day), odds ratio (OR)=0.62, 95% Confidence Interval (CI)=0.49 – 0.79); the inverse association was strongest for serous borderline and mucinous tumors. High intake of total vitamin D was not associated overall with ovarian cancer risk, but was inversely associated with risk of serous borderline (Q4, >559 IU/day vs. Q1, <164 IU/day, OR=0.51, 95% CI=0.34–0.76) and endometrioid tumors (Q4 vs. Q1, OR=0.55, 95% CI=0.39-0.80). We found no evidence that lactose intake influenced ovarian cancer risk, or that risk varied by tumor aggressiveness in the analyses of intake of dairy foods and nutrients. The overall inverse association with high intake of calcium, and the inverse associations of calcium and vitamin D with specific histological subtypes warrant further investigation.

Background

Single nucleotide polymorphisms (SNPs) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies.

Methods

We conducted a pooled analysis of previously-identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kilobases of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset.

Results

After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk.

Conclusions

Common variants in these evaluated genes do not appear to be strongly associated with EOC risk.

Impact

This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be performed, and use of imputed SNP data should be considered.

Folate, methionine, vitamin B6, and vitamin B12 may influence carcinogenesis due to their roles in the one-carbon metabolism pathway which is critical for DNA synthesis, methylation, and repair. Low intake of these nutrients has been associated with an increased risk of breast, colon, and endometrial cancers. Previous studies that have examined the relation between these nutrients and ovarian cancer risk have been inconsistent and have had limited power to examine the relation by histologic subtype. We investigated the association between folate, methionine, vitamin B6, vitamin B12, and alcohol among 1910 women with ovarian cancer and 1989 controls from a case-control study conducted in eastern Massachusetts and New Hampshire from 1992 to 2008. Diet was assessed via food frequency questionnaire. Participants were asked to recall diet one-year before diagnosis or interview. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). We also examined whether the associations varied by ovarian cancer histologies using polytomous logistic regression. We observed an inverse association between dietary vitamin B6 (covariate-adjusted OR=0.76, 95% CI 0.64–0.92; ptrend=0.002) and methionine intake (covariate-adjusted OR=0.72, 95% CI=0.60–0.87; ptrend<0.001) and ovarian cancer risk comparing the highest to lowest quartile. The association with dietary vitamin B6 was strongest for serous borderline (covariate-adjusted OR=0.49, 95% CI=0.32–0.77; ptrend=0.001) and serous invasive (covariate-adjusted OR=0.74, 95% CI=0.58–0.94; ptrend=0.012) subtypes. Overall, we observed no significant association between folate and ovarian cancer risk. One-carbon metabolism related nutrients, especially vitamin B6 and methionine, may lower ovarian cancer risk.

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with (p = 0.001) and clear cell EOC. Gene associations with histotypes at< 0.05 included:(p = 0.005 and = 0.008, serous and high-grade serous, respectively), (p = 0.035, endometrioid and mucinous), (p = 0.03, mucinous), (p = 0.022, clear cell), (p = 0.021 endometrioid) and (p = 0.017 and = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Background

We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003).

Methods

We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium.

Results

No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies.

Conclusions

Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.

Impact

Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.

Inflammation and non-steroidal anti-inflammatory agents (NSAIDs) may play important role in ovarian cancer. However, epidemiologic data are inconsistent, possibly reflecting inter-individual genetic differences affecting the metabolism of NSAIDs. We examined whether common polymorphisms affecting the metabolism of NSAIDs modify the association between NSAIDs and ovarian cancer risk. We genotyped 1,353 DNA samples from women who developed ovarian cancer and 1,823 samples from matched controls participating in the New England Case-Control study and the Nurses' Health Studies. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with regular use of NSAIDs and with relevant polymorphisms on ovarian cancer risk. Multivariable unconditional logistic regression estimated the association of NSAID use across stratum of each genotype. Regular use of NSAIDs was not associated with ovarian cancer risk. Multivariable OR (95% CI) associated with use NSAIDs was 0.85 (95% CI: 0.71-1.02). Associations between NSAID use and ovarian cancer risk did not differ significantly across strata of genotypes. None of the studied polymorphisms was associated with ovarian cancer risk. The multivariable ORs (95% CI) associated with CYP2C9 and UGT1A6 variant genotypes were 0.99 (0.90-1.08) and 0.93 (0.82-1.05), respectively. The multivariable ORs (95% CI) associated with PPAR-γ, COX-2 -765G>C, and COX-2 Ex10+837T>C polymorphisms were 1.02 (0.87-1.20), 0.87 (0.75-1.00), and 0.97 (0.87-1.09), respectively. In this relatively large study, we found no convincing evidence supporting an association between NSAIDs use and ovarian cancer risk. Furthermore, data did not suggest interaction between selected polymorphisms and use of NSAIDs in relation to ovarian cancer risk.

Differentiating ovarian tumors based on developmental pathway may further our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (NECC) and two cohort studies (NHS/NHSII) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and non-dominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid, or clear cell, whereas non-dominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis, and age were more strongly associated with dominant (RRs = 0.60, 0.83, 1.58, 1.37, respectively) than non-dominant tumors (RRs = 1.03, 0.93, 0.84, 1.14 p-difference = 0.0001, 0.01, 0.0003, 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

Objective

To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism (SNP) and the PROGINS allele.

Design

Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies.

Setting

An international ovarian cancer consortium including studies from the Australia, Europe and the United States,

Patients

5,812 White female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies.

Interventions

None.

Main Outcome Measures

Genotypes for the +331C/T SNP and PROGINS allele and a history of endometriosis.

Results

The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (OR=0.65; 95% CI: 0.43–0.98, p=0.042), whereas there was no association between the PROGINS allele and endometriosis (OR=0.94, 95% CI 0.76, 1.16).

Conclusions

Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced PR-A to PR-B ratio and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.