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ABSTRACT: Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however little is known about whether these associations vary by surgical characteristics, individual characteristics, or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy, and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case-Control study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer (OR: 0.82, 95%CI: 0.68-0.97), especially for endometrioid tumors (OR=0.45, 95%CI: 0.29-0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR=0.60, 95%CI: 0.42-0.84) rather than at a later time (OR=0.93, 95%CI: 0.75-1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95%CI: 0.83, 1.42), although it was associated with a non-significant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95%CI: 0.40, 1.02) or within the last 10 years (OR=0.65, 95%CI: 0.38, 1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR=0.65, 95%CI: 0.45-0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population-based case-control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk. © 2013 Wiley Periodicals, Inc.
International Journal of Cancer 05/2013; · 5.44 Impact Factor
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Hui Shen,
Brooke L Fridley,
Honglin Song,
Kate Lawrenson,
Julie M Cunningham,
Susan J Ramus,
Mine S Cicek,
Jonathan Tyrer,
Douglas Stram,
Melissa C Larson, [......],
Joellen M Schildkraut,
Thomas A Sellers,
David Huntsman,
Andrew Berchuck,
Georgia Chenevix-Trench,
Simon A Gayther,
Paul D P Pharoah,
Peter W Laird,
Ellen L Goode,
Celeste Leigh Pearce
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ABSTRACT: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Nature Communications 03/2013; 4:1628. · 7.40 Impact Factor
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Paul D P Pharoah,
Ya-Yu Tsai,
Susan J Ramus,
Catherine M Phelan,
Ellen L Goode,
Kate Lawrenson,
Melissa Buckley,
Brooke L Fridley,
Jonathan P Tyrer,
Howard Shen, [......],
Per Hall,
Douglas F Easton,
Celeste L Pearce,
Andrew Berchuck,
Georgia Chenevix-Trench,
Edwin Iversen,
Alvaro N A Monteiro,
Simon A Gayther,
Joellen M Schildkraut,
Thomas A Sellers
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ABSTRACT: Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Nature Genetics 03/2013; 45(4):362-370. · 35.53 Impact Factor
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Stig E Bojesen,
Karen A Pooley,
Sharon E Johnatty,
Jonathan Beesley,
Kyriaki Michailidou,
Jonathan P Tyrer,
Stacey L Edwards,
Hilda A Pickett,
Howard C Shen,
Chanel E Smart, [......],
Simon A Gayther,
Paul D P Pharoah,
Roger R Reddel,
Ellen L Goode,
Mark H Greene,
Douglas F Easton,
Andrew Berchuck,
Antonis C Antoniou,
Georgia Chenevix-Trench,
Alison M Dunning
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ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
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Jennifer Permuth-Wey,
Kate Lawrenson,
Howard C Shen,
Aneliya Velkova,
Jonathan P Tyrer,
Zhihua Chen,
Hui-Yi Lin,
Y Ann Chen,
Ya-Yu Tsai,
Xiaotao Qu, [......],
Catherine M Phelan,
Edwin Iversen,
Joellen M Schildkraut,
Andrew Berchuck,
Brooke L Fridley,
Ellen L Goode,
Paul D P Pharoah,
Alvaro N A Monteiro,
Thomas A Sellers,
Simon A Gayther
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ABSTRACT: Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Nature Communications 03/2013; 4:1627. · 7.40 Impact Factor
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ABSTRACT: PURPOSE: Common analgesics (aspirin, non-aspirin NSAIDs, and acetaminophen) may be associated with hormone-related cancers, possibly via effects on sex hormone and prolactin concentrations. METHODS: Between 1996 and 1999, 29,611 participants in the Nurses' Health Study II (NHSII) provided blood samples; 18,521 provided samples timed in the early follicular and mid-luteal phases of the menstrual cycle, the remainder provided untimed samples. We assessed the cross-sectional relationship between analgesic use and plasma sex hormone and prolactin concentrations among 2,034 premenopausal women, 32-54 years old, who served as controls in nested case-control studies, or participated in a within-person hormone reproducibility study in the NHSII; this included 1,700 timed and 334 untimed samples. Estrogens and progesterone were measured in timed samples; androgens and prolactin were measured in timed and untimed samples. RESULTS: In multivariable models, non-aspirin NSAIDs were positively associated with follicular free estradiol [13.5 % higher, use ≥4 days/week vs. nonusers (p = 0.04; p trend = 0.11)]; results for follicular total estradiol were similar (13.2 % higher, p = 0.06; p trend = 0.11). Acetaminophen use was inversely associated with prolactin (11.8 % lower, use 2 days/week vs. nonusers, p = 0.01, p trend = 0.04). Acetaminophen was also inversely associated with free testosterone (7.1 % lower, use 2 days/week vs. nonusers, p = 0.04; p trend = 0.04). No other associations were observed with the other hormones, or with aspirin use. CONCLUSIONS: There were no clear patterns between analgesic use and sex hormones in premenopausal women. Acetaminophen use may be modestly associated with prolactin and free testosterone. Our results do not support that analgesic use influences cancer risk through alterations in premenopausal circulating sex hormones or prolactin.
Cancer Causes and Control 03/2013; · 2.88 Impact Factor
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ABSTRACT: BACKGROUND: Acrylamide is a probable human carcinogen formed during cooking of starchy foods. Two large prospective cohort studies of dietary acrylamide intake and ovarian cancer risk observed a positive association, although two other studies reported no association. METHODS: We measured acrylamide exposure using red blood cell acrylamide and glycidamide hemoglobin adducts among women in two large prospective cohorts: the Nurses' Health Study and Nurses' Health Study II. Between blood collection and 2010, we identified 263 incident cases of epithelial ovarian cancer, matching two controls per case. We used logistic regression models to examine the association between acrylamide exposure and ovarian cancer risk, adjusting for matching factors, family history of ovarian cancer, tubal ligation, oral contraceptive use, body mass index (BMI), parity, alcohol intake, smoking, physical activity, and caffeine intake. RESULTS: The multivariate-adjusted relative risk (RR) of ovarian cancer comparing the highest versus lowest tertile of total acrylamide adducts was 0.79 (95% CI: 0.50-1.24, P trend = 0.08). The comparable RR of ovarian cancer among non-smokers at blood draw was 0.85 (95% CI: 0.57-1.27, P trend =0.14). The association did not differ by tumor histology (serous invasive versus not), P for heterogeneity=0.41. Individual adduct types (acrylamide or glycidamide) were not associated with risk. CONCLUSIONS: We observed no evidence that acrylamide exposure as measured by adducts to hemoglobin is associated with an increased risk of ovarian cancer. Impact: Our finding indicates that acrylamide intake may not increase risk of ovarian cancer.
Cancer Epidemiology Biomarkers & Prevention 02/2013; · 4.12 Impact Factor
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ABSTRACT: 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.
International Journal of Cancer 01/2013; · 5.44 Impact Factor
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Elizabeth M Poole,
Melissa A Merritt,
Susan J Jordan,
Hannah P Yang,
Susan E Hankinson,
Yikyung Park,
Bernard A Rosner,
Penelope M Webb,
Daniel W Cramer,
Nicolas Wentzensen,
Kathryn L Terry, Shelley S Tworoger
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ABSTRACT: BACKGROUND: Approximately half of epithelial ovarian cancers are fatal within three years; however about 35% of women survive at least ten years. In the Nurses' Health Study, New England Case-Control Study, Australian Ovarian Cancer Study, and NIH-AARP Diet and Health Study, we investigated potential differences in the associations with ovarian cancer risk factors by tumor aggressiveness, defined based on time from diagnosis until death. METHODS: We calculated relative risks (RR) and 95% confidence intervals (CI) for associations of known or suspected ovarian cancer risk factors with rapidly fatal (death within three years of diagnosis) and less aggressive tumors (all others) using Cox proportional hazards competing risks analysis (NHS, AARP) or polytomous logistic regression (NECC, AOCS). Results were combined using random effects meta-analysis. RESULTS: Increasing age was associated with greater risk of rapidly fatal versus less aggressive disease (OR, 5-yr increase: 1.39; 95%CI: 1.29-1.49 vs. OR: 1.09; 95%CI: 1.03-1.16, respectively; p-diff<0.0001). OC use was associated with a greater decreased risk of rapidly fatal (OR, 5-yr increase: 0.69; 95% CI: 0.58-0.82) versus less aggressive disease (OR: 0.81; 95%CI: 0.74-0.89; p-diff=0.002). Conversely, increasing parity was associated only with less aggressive disease (OR, per child: 0.87; 95%CI: 0.81-0.93). CONCLUSION: In this analysis of 4,342 cases, there were clear differences in risk factors for rapidly fatal vs. less aggressive ovarian tumors. Impact: Differences in risk factor associations by tumor aggressiveness suggests the developmental pathways through which the tumors develop and may be important for developing primary prevention strategies for the most aggressive cancers.
Cancer Epidemiology Biomarkers & Prevention 01/2013; · 4.12 Impact Factor
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ABSTRACT: Plasma estrogen and androgen levels are positively associated with postmenopausal breast cancer risk, but how long a single blood measurement can predict risk and whether the associations vary by tumor hormone receptor status remain unclear. We conducted nested case-control analyses within the Nurses' Health Study. Blood samples were collected in 1989-1990 and again in 2000-2002. Among postmenopausal women not using postmenopausal hormones at blood collection, 707 cases were diagnosed through June 2010, with two matched controls per case. We used unconditional logistic regression analyses to estimate the relative risks controlling for other breast cancer risk factors. The intra-class correlation coefficients for two blood measurements collected 10 years apart ranged from 0.54 (dehydroepiandrosterone sulfate, DHEAS) to 0.74 (sex hormone-binding globulin, SHBG). Overall, women in the top (vs. bottom) 25 % of levels of estradiol, free estradiol, testosterone, free testosterone, and DHEAS were at a 50-110 % higher risk of breast cancer (p (trend) < 0.001). SHBG was inversely associated with risk (p (trend) = 0.004). RRs were similar when comparing cases diagnosed 1-10 versus 11-20 years (or 16-20 years) after blood collection (p (interaction) > 0.2). Except for DHEAS, the associations varied significantly by hormone receptor status (p (heterogeneity) ≤ 0.02). For example, the RRs (95 % CIs) comparing the highest versus lowest quartile were 2.8 (2.0-4.0; p (trend) < 0.001) for ER +/PR + tumors versus 1.1 (0.6-2.1; p (trend) = 0.98) for ER-/PR- tumors for estradiol, and 1.8 (1.3-2.5; p (trend) < 0.001) versus 0.6 (0.3-1.2; p (trend) = 0.35) for testosterone. One measure of circulating sex hormones in postmenopausal women can predict risk of hormone receptor positive breast cancer for up to 16-20 years.
Breast Cancer Research and Treatment 01/2013; · 4.43 Impact Factor
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Hui Shen,
Brooke L. Fridley,
Honglin Song,
Kate Lawrenson,
Julie M. Cunningham,
Susan J. Ramus,
Mine S. Cicek,
Jonathan Tyrer,
Douglas Stram,
Melissa C. Larson, [......],
Joellen M. Schildkraut,
Thomas A. Sellers,
David Huntsman,
Andrew Berchuck,
Georgia Chenevix-Trench,
Simon A. Gayther,
Paul D. P. Pharoah,
Peter W. Laird,
Ellen L. Goode,
Celeste Leigh Pearce
Nat Commun. 01/2013; 4:1628.
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Dominique S Michaud,
Afshan Siddiq,
David G Cox,
Danielle M Backes,
Federico C F Calboli,
Michael E Sughrue,
J Michael Gaziano,
Jing Ma,
Meir Stampfer, Shelley S Tworoger,
David J Hunter,
Carlos A Camargo,
Andrew T Parsa
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ABSTRACT: The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.
To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.
A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99-2.54), compared to those homozygous for the wild type allele.
Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.
PLoS ONE 01/2013; 8(4):e61117. · 4.09 Impact Factor
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Jennifer H Lin,
Shumin M Zhang,
Kathryn M Rexrode,
Joann E Manson,
Andrew T Chan,
Kana Wu, Shelley S Tworoger,
Susan E Hankinson,
Charles Fuchs,
J Michael Gaziano,
Julie E Buring,
Edward Giovannucci
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ABSTRACT: BACKGROUND & AIMS: There is observational and clinical evidence that indicate that sex hormones affect development of colorectal cancer (CRC) in men and women. However, the relationship between endogenous sex hormone levels and CRC is unclear. METHODS: We collected data on lifestyle, medical history, and diet etc. (through 2008), along with blood samples, from the Nurses' Health Study, the Women's Health Study, the Health Professional Follow-Up Study, and the Physicians' Health Study II. We measured plasma levels of estrone, estradiol, testosterone, sex hormone binding globulin (SHBG), and c-peptide among 730 women (293 cases of CRC and 437 healthy individuals, as controls) and 1158 men (439 CRC cases and 719 controls), and used unconditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were 2-sided. RESULTS: Total testosterone, SHBG, and the ratio of estradiol to testosterone were associated with CRC in men after adjustments for matching and risk factors for CRC, including BMI and plasma levels of C-peptide. The RRs in the highest relative to the lowest quartile were 0.62 for testosterone (95% CI, 0.40-0.96), 0.65 for SHBG (95% CI, 0.42-0.99), and 2.63 for the ratio (95% CI, 1.58-4.36) (P-values for trend ≤0.02). However, in women, only the ratio of estradiol to testosterone was (inversely) associated with CRC after adjustments for all factors (RR, 0.43; 95% CI, 0.22-0.84; P-value for trend, .03). CONCLUSIONS: Based on combined data from 4 population studies, there appears to be an association between levels of sex hormones and CRC risk in men. There also appears to be an inverse association between the ratio of estradiol to testosterone and CRC in postmenopausal women.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2012; · 5.64 Impact Factor
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ABSTRACT: Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case-control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989-1990 (NHS) or in 1996-1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF-1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI <25 kg/m(2), but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women.
Breast Cancer Research and Treatment 10/2012; · 4.43 Impact Factor
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Elizabeth M Poole,
Margaret A Gates,
Brigit A High,
Stephen J Chanock,
Daniel W Cramer,
Julie M Cunningham,
Brooke L Fridley,
Simon A Gayther,
Ellen L Goode,
Edwin S Iversen, [......],
Susan J Ramus,
Joellen M Schildkraut,
Rebecca Sutphen,
Ya-Yu Tsai,
Jonathan Tyrer,
Robert A Vierkant,
Nicolas Wentzensen,
Hannah P Yang,
Kathryn L Terry, Shelley S Tworoger
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ABSTRACT: Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.
In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.
Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.
Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.
Cancer Causes and Control 09/2012; 23(11):1805-10. · 2.88 Impact Factor
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ABSTRACT: BACKGROUND: Early life body size and circulating levels of IGF-1 and IGFBP-3 have been linked to increased risks of breast and other cancers, but it is unclear whether these exposures act through a common mechanism. Previous studies have examined the role of IGF-1 and IGFBP-3 genetic variation in relation to adult height and body size, but few studies have examined associations with birthweight and childhood size. METHODS: We examined whether htSNPs in IGF-1 and the IGFBP-1/IGFBP-3 gene region are associated with the self-reported outcomes of birthweight, body fatness at ages 5 and 10, and body mass index (BMI) at age 18 among healthy women from the Nurses' Health Study (NHS) and NHSII. We used ordinal logistic regression to model odds ratios (ORs) and 95% confidence intervals (CI) of a one category increase for birthweight and somatotypes at ages 5 and 10. We used linear regression to model associations with BMI at age 18. RESULTS: Among 4567 healthy women in NHS and NHSII, we observed no association between common IGF-1 or IGFBP-1/IGFBP-3 SNPs and birthweight, body fatness at ages 5 and 10, or BMI at age 18. CONCLUSIONS: Common IGF-1 and IGFBP-1/IGFBP-3 SNPs are not associated with body size in early life.
BMC Public Health 08/2012; 12(1):659. · 2.00 Impact Factor
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ABSTRACT: Estrogen metabolism profiles may play an important role in the relationship between body size and breast carcinogenesis. Previously, we observed inverse associations between current body mass index (BMI) and plasma levels of parent estrogens (estrone and estradiol) among premenopausal women during both follicular and luteal phases. Using data from the Nurses' Health Study II, we assessed whether height, current BMI, and BMI at age 18 were associated with the urinary concentrations of 15 estrogens and estrogen metabolites (jointly referred to as EM) measured during the luteal phase among 603 premenopausal women. We observed inverse associations with total EM for height (P (trend) = 0.01) and current BMI (P (trend) = 0.01), but not BMI at age 18 (P (trend) = 0.26). Six EMs were 18-27 % lower in women with a height 68+ versus ≤62 in., primarily in the methylated catechol pathway (P (trend) = 0.04). Eight EMs were 18-50 % lower in women with a BMI of 30+ versus <20, primarily in the 2-catechol and methylated catechol pathways (P (trend) < 0.001 for both). Our results suggest that height and current BMI are associated with estrogen metabolism profiles in premenopausal women. Further studies with timed urine and blood collections are required to confirm and extend our findings.
Hormones and Cancer 08/2012;
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ABSTRACT: 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.
Two prospective cohort studies and a case-control study.
Academic institution.
A total of 992 cases and 1,050 population-based control samples from a New England case-control study and 240 cases and 900 control samples from the Nurses' Health Studies.
None.
Genotyping of the N314D variant and the 4-bp deletion (-119delGTCA) of GALT with the use of 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).
Logistic regression analysis identified no association between D1/D2 genotypes and ovarian cancer risk (pooled risk ratio 1.1 [95% confidence interval (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.
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.
Fertility and sterility 06/2012; 98(3):687-91. · 3.97 Impact Factor
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ABSTRACT: The purpose of this meta-analysis was to determine the strength of the association between gynecologic surgeries, tubal ligation and hysterectomy, and ovarian cancer.
We searched the PubMed, Web of Science, and Embase databases for all English-language articles dated between 1969 through March 2011 using the keywords "ovarian cancer" and "tubal ligation" or "tubal sterilization" or "hysterectomy." We identified 30 studies on tubal ligation and 24 studies on hysterectomy that provided relative risks for ovarian cancer and a p-value or 95% confidence interval (CI) to include in the meta-analysis. Summary RRs and 95% CIs were calculated using a random-effects model.
The summary RR for women with vs. without tubal ligation was 0.70 (95%CI: 0.64, 0.75). Similarly, the summary RR for women with vs. without hysterectomy was 0.74 (95%CI: 0.65, 0.84). Simple hysterectomy and hysterectomy with unilateral oophorectomy were associated with a similar decrease in risk (summery RR = 0.62, 95%CI: 0.49-0.79 and 0.60, 95%CI: 0.47-0.78, respectively). In secondary analyses, the association between tubal ligation and ovarian cancer risk was stronger for endometrioid tumors (summary RR = 0.45, 95%CI: 0.33, 0.61) compared to serous tumors.
Observational epidemiologic evidence strongly supports that tubal ligation and hysterectomy are associated with a decrease in the risk of ovarian cancer, by approximately 26-30%. Additional research is needed to determine whether the association between tubal ligation and hysterectomy on ovarian cancer risk differs by individual, surgical, and tumor characteristics.
Journal of Ovarian Research 05/2012; 5(1):13. · 2.57 Impact Factor
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ABSTRACT: Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans.
We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type.
In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type.
Higher IGF-1 levels and a greater IGF-1:IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of insulin-like growth factors in the structure of breast lobules and lobular involution.
Breast cancer research: BCR 03/2012; 14(2):R44. · 5.24 Impact Factor
