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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 ( = 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 < 7.94 × 10. 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 , and . 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.
©2018 American Association for Cancer Research.
Large-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 -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 < 2.2 × 10, we identified 35 genes, including at 11q14.2 (Z = 5.08, = 3.83 × 10, 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 ( < 1.47 × 10). These data identify one novel locus ) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. .
©2018 American Association for Cancer Research.
OBJECTIVE - Homologous recombination (HR)-proficient ovarian tumors have poorer clinical outcomes and show resistance to poly ADP ribose polymerase inhibitors (PARPi). A subset of HR-proficient ovarian tumors show amplification in bromodomain and extra-terminal (BET) genes such as BRD4. We aimed to test the hypothesis that BRD4 inhibition sensitizes ovarian cancer cells to PARPi by reducing HR efficiency and increasing DNA damage.
METHODS - HR-proficient ovarian cancer cell lines (OVCAR-3, OVCAR-4, SKOV-3, UWB1.289+BRCA1) were treated with BRD4-targeting siRNA, novel (INB054329, INCB057643) and established (JQ1) BET inhibitors (BETi) and PARPi (olaparib, rucaparib). Cell growth and viability were assessed by sulforhodamine B assays in vitro, and in SKOV-3 and ovarian cancer patient-derived xenografts in vivo. DNA damage and repair (pH2AX, RAD51 and BRCA1 foci formation, and DRGFP HR reporter activity), apoptosis markers (cleaved PARP, cleaved caspase-3, Bax) and proliferation markers (PCNA, Ki67) were assessed by immunofluorescence and western blot.
RESULTS - In cultured cells, inhibition of BRD4 by siRNA or INCB054329 reduced expression and function of BRCA1 and RAD51, reduced HR reporter activity, and sensitized the cells to olaparib-induced growth inhibition, DNA damage induction and apoptosis. Synergy was observed between all BETi tested and PARPi. INCB054329 and olaparib also co-operatively inhibited xenograft tumor growth, accompanied by reduced BRCA1 expression and proliferation, and increased apoptosis and DNA damage.
CONCLUSIONS - These results provide strong rationale for using BETi to extend therapeutic efficacy of PARPi to HR-proficient ovarian tumors and could benefit a substantial number of women diagnosed with this devastating disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
BACKGROUND - High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.
METHODS - We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.
RESULTS - Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53).
CONCLUSIONS - These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.
OBJECTIVE - Blood type A and the A1 allele have been associated with increased ovarian cancer risk. With only two small studies published to date, evidence for an association between ABO blood type and ovarian cancer survival is limited.
METHODS - We conducted a retrospective cohort study of Tumor Registry confirmed ovarian cancer cases from the Vanderbilt University Medical Center with blood type from linked laboratory reports and ABO variants from linked Illumina Exome BeadChip data. Associations with overall survival (OS) were quantified by hazard ratios (HR) and confidence intervals (CI) from proportional hazards regression models; covariates included age, race, stage, grade, histologic subtype, and year of diagnosis.
RESULTS - ABO phenotype (N = 694) and/or genotype (N = 154) data were available for 713 predominantly Caucasian (89.3%) cases. In multivariable models, blood type A had significantly better OS compared to either O (HR: 0.75, 95% CI: 0.60-0.93) or all non-A (HR: 0.77, 95% CI: 0.63-0.94) cases. Similarly, missense rs1053878 minor allele carriers (A2) had better OS (HR: 0.50, 95% CI: 0.25-0.99). Among Caucasians, this phenotype association was strengthened, but the genotype association was attenuated; instead, four variants sharing moderate linkage disequilibrium with the O variant were associated with better OS (HR: 0.62, 95% CI: 0.39-0.99) in unadjusted models.
CONCLUSIONS - Blood type A was significantly associated with longer ovarian cancer survival in the largest such study to date. This finding was supported by genetic analysis, which implicated the A2 allele, although O related variants also had suggestive associations. Further research on ABO and ovarian cancer survival is warranted.
BACKGROUND - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited.
METHODS - Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths).
RESULTS - Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98)).
CONCLUSIONS - Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
BACKGROUND - Thrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted.
METHODS - We selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995-2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 × 10(9)/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease.
RESULTS - Pre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8-53.2 %, 31.6-39.4 %, and 19.9-26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97-2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25-3.23).
CONCLUSIONS - Our EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis.
OBJECTIVE - Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib.
METHODS - Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 in ovarian tumors and cell lines were extracted from The Cancer Genome Atlas (TCGA) and Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). In HR-proficient ovarian cancer cell line models (OVCAR-3, OVCAR-4, SKOV-3, and UWB1.289+BRCA1 wild-type), cell growth and viability were assessed by sulforhodamine B and xenograft assays. DNA damage and repair (pH2AX and RAD51 co-localization and DRGFP reporter activity) and apoptosis (cleaved PARP and cleaved caspase-3) were assessed by immunofluorescence and Western blot assays.
RESULTS - TCGA and CCLE data revealed positive correlations (Spearman) between cyclin E E2F1, and E2F1 gene targets related to DNA repair (BRCA1 and RAD51). Panobinostat downregulated cyclin E and HR repair pathway genes, and reduced HR efficiency in cyclin E-amplified OVCAR-3 cells. Further, panobinostat synergized with olaparib in reducing cell growth and viability in HR-proficient cells. Similar co-operative effects were observed in xenografts, and on pharmacodynamic markers of HR repair, DNA damage and apoptosis.
CONCLUSIONS - These results provide preclinical rationale for using HDACi to reduce HR in cyclin E-overexpressing and other types of HR-proficient ovarian cancer as a means of enhancing PARPi activity.
Copyright © 2016 Elsevier Inc. All rights reserved.