| 1. |
- Yang, Yaohua, et al.
(author)
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Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
- 2019
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In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:3, s. 505-517
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Journal article (peer-reviewed)abstract
- DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
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| 2. |
- Lu, Yingchang, et al.
(author)
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
- 2018
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
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Journal article (peer-reviewed)abstract
- .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
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| 3. |
- Fortner, Renee T., et al.
(author)
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Ovarian Cancer Risk Factor Associations by Primary Anatomic Site : The Ovarian Cancer Cohort Consortium
- 2020
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 29:10, s. 2010-2018
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Journal article (peer-reviewed)abstract
- Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites.Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests.Results: Most associations did not vary by tumor site (P-het = 0.05). Associations between first pregnancy (P-het = 0.04), tubal ligation (P-het = 0.01), and early-adult (age 18-21 years) body mass index (BMI; P-het = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (P-het = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases.Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site.Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
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| 4. |
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| 5. |
- Trabert, Britton, et al.
(author)
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The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles : An Analysis from the Ovarian Cancer Cohort Consortium (OC3)
- 2020
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In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 80:5, s. 1210-1218
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Journal article (peer-reviewed)abstract
- Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies.
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