Serous Epithelial Ovarian Cancer Risk Research Articles

Utility of Preoperative Inflammatory Markers to Distinguish Epithelial Ovarian Cancer from Benign Ovarian Masses.

Background: Inflammatory markers have been reported to be predictors for the presence of epithelial ovarian cancer (EOC), however, the cut-off value of each marker remains unclear and predictive capability of the markers in different histology types of EOC is still unknown.Methods: A total of 207 patients with benign ovarian masses and 887 EOC patients who underwent surgical resection, and were pathologically diagnosed were included. We compared the difference of preoperative inflammatory markers between benign ovarian masses and EOC patients. Stratified analysis by histology subtype was further conducted. Logistic regression analyses and receiver operating characteristic (ROC) curves was used to evaluate the predictive capability of the markers.Results: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were significantly associated with all stages and subtypes of EOC (P<0.001). The optimal cut-off points based on ROC curve analyses for NLR, PLR, and LMR were found to be 2.139 (AUC=0.749, P<0.001), 182.698 (AUC=0.730, P<0.001), and 3.619 (AUC = 0.709, P<0.001), respectively. In low CA125 level patients, high level of NLR and PLR increase the risk of endometrioid EOC, while low level of LMR were significantly associated with an increased risk of serous EOC.Conclusions: In addition to CA125, NLR, PLR, and LMR could be used as predictors of EOC and preoperative inflammatory markers may be used as a potential biomarker for predicting different histotypes of EOC.

Abstract 606: Circulating proteins associated with ovarian cancer risk and survival are enriched for immune-related pathways

Abstract Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and five-year survival rates in this group continue to remain very poor. Circulating proteins may illuminate EOC etiology and have the potential to serve as biomarkers for early detection and diagnosis. We performed a two-sample Mendelian randomization (MR) study with circulating protein levels as exposures and susceptibility to EOC and its histological subtypes as outcomes. We used previously identified quantitative trait loci (QTLs) robustly associated with plasma levels of 1,478 proteins as genetic instruments and corresponding summary genetic association statistics for these instruments derived from 22,406 EOC cases and 40,941 controls. Among proteins that had only a single QTL variant available as a genetic instrument, we identified 12 proteins whose circulating levels were associated with overall EOC risk at a False Discovery Rate (FDR) of &amp;lt; 0.1. For nine of the 12 proteins, the association was driven by variants near ABO, which is both a genome-wide significant high grade serous histotype risk locus and a hub QTL for several proteins. Three of these 12 proteins and their QTLs were, however, not linked to the ABO locus and included the products of the NOTCH signaling genes MFAP2 and DLK1. Among proteins that had multiple QTL variants available for the creation of more robust multi-variant genetic instruments, we identified 33 protein level-EOC risk associations at FDR &amp;lt; 0.1. Once again, we observed that the majority of associations (19/33) were driven by variants at the ABO locus. Nine of the 14 remaining associations were for overall and high grade serous EOC risk and included predominantly immune system proteins: ARTS1 (HLA class I), CPNE1 (involved in innate immunity), Macrophage mannose receptor (HLA class I), DQA2 (HLA class II), RGAP1 (innate immunity), Cathepsin H (innate immunity), and FCG2B (the low affinity receptor for the Fc region of immunoglobulin gamma). We observed one mucinous histotype-specific association (complement C4) and two clear cell histotype-specific associations (KI2S2 and PSG4). KI2S2 is a Killer cell immunoglobulin-like receptor expressed by natural killer cells and PSG4 is a member of the carcinoembryonic antigen gene family that also includes the gene encoding the tumor marker for colorectal cancer. Finally, we also performed two-sample MR analyses using survival as the outcome and identified two proteins whose plasma levels were associated with overall EOC survival at FDR &amp;lt; 0.1: SULT1E, a phenol sulfotransferase that conjugates sulfates to estrogens, and MA2B2. Thus, we identified circulating proteins that are candidate biomarkers for EOC risk and survival. They represent promising starting points for follow-up studies and the measurement of plasma levels of these proteins in EOC cohorts is required to validate these associations. Citation Format: Daniel P. Considine. Circulating proteins associated with ovarian cancer risk and survival are enriched for immune-related pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 606.

Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

ObjectiveGenome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. MethodsGenotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. ResultsAt chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10−9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10−9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10−8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10−7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10−7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10−7). ConclusionWhile some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10−6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer

The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants.

Effects of BRCA1 Knockdown on CYP19a1/Aromatase and Steroid Receptor Expression in Ovarian and Tubal Cells

BRCA1 mutation carriers have an increased lifetime risk of serous epithelial ovarian cancer (EOC), as well as breast cancer, but reasons for this increased risk remain elusive. We hypothesized that the reported relationship between cytochrome P450 aromatase (CYP19a1) and BRCA1 expression might be used to elucidate this pathway to EOC in women with BRCA1 mutations. Expression of BRCA1, CYP19a1 and steroid receptors was measured by qRT-PCR and immunoblotting in immortalized cell lines from the ovarian surface epithelium (hOSE17-1 and hOSE11-12), tubal epithelium (OE-E6/E7) and granulosa cell tumor (KGN), as well as MCF-7 mammary carcinoma cells, before and after BRCA1 knockdown with 2 nM siRNA, or stimulation of CYP19a1 expression with forskolin or phorbol-12-myristate-13-acetate (PMA). Low or no CYP19a1 expression was observed in all cell lines, except KGN cells. BRCA1 knockdown with 2 nM siRNA did not stimulate CYP19a1 expression in any cell line. Forskolin treatment increased CYP19a1 expression only in KGN cells and this resulted in a decrease in BRCA1 expression equivalent to 2 nM siRNA knockdown. We conclude that lowering BRCA1 expression in OSE and tubal epithelia cell lines does not stimulate CYP19a1 expression or change steroid receptor expression significantly. The mechanism by which BRCA1 mutation increases risk of serous EOC remains to be elucidated.

Effect of tubal sterilization technique on risk of serous epithelial ovarian and primary peritoneal carcinoma

ObjectiveTo determine the effect of excisional tubal sterilization on subsequent development of serous epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC). MethodsWe performed a population-based, nested case–control study using the Rochester Epidemiology Project. We identified all patients with a diagnosis of serous EOC or PPC from 1966 through 2009. Each case was age-matched to 2 controls without either diagnosis. Odds ratios (ORs) and corresponding 95% CIs were estimated from conditional logistic regression models. Models were adjusted for prior hysterectomy, prior salpingo-oophorectomy, oral contraceptive use, endometriosis, infertility, gravidity, and parity. ResultsIn total, we identified 194 cases of serous EOC and PPC during the study period and matched them with 388 controls (mean [SD] age, 61.4 [15.2] years). Fourteen cases (7.2%) and 46 controls (11.9%) had undergone tubal sterilization. Adjusted risk of serous EOC or PPC was slightly lower after any tubal sterilization (OR, 0.59 [95% CI, 0.29–1.17]; P=.13). The rate of excisional tubal sterilization was lower in cases than controls (2.6% vs 6.4%). Adjusted risk of serous EOC and PPC was decreased by 64% after excisional tubal sterilization (OR, 0.36 [95% CI, 0.13–1.02]; P=.054) compared with those without sterilization or with nonexcisional tubal sterilization. ConclusionsWe present a population-based investigation of the effects of excisional tubal sterilization on the risk of serous EOC and PPC. Excisional methods may confer greater risk reduction than other sterilization methods.

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Inherited common variants in mitochondrial DNA and invasive serous epithelial ovarian cancer risk

BackgroundMitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk.MethodsA panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n = 405) and frequency age-matched controls (n = 445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher’s exact test.ResultsThe most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR = 4.84, 95% CI: 1.03–22.68, P = 0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value < 0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%.ConclusionCommon European MT-SNPs (MAF > 5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF < 5%) in invasive serous OvCa risk.

Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

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 binding site 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 (OR=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 associates 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.

Abstract 1649: Genome-wide association study of copy number variations in serous epithelial ovarian cancer susceptibility

Abstract DNA copy number variations (CNVs) are a significant and ubiquitous source of human genetic variation. However, the influence of CNVs on cancer susceptibility remains poorly understood. Out of 83 genome-wide association studies (GWAS) on cancer to date, only a few studies found significant associations on germline CNVs and cancer. Here we analyzed data from our ongoing two-stage GWAS of four North American case-control studies to test the hypothesis that CNVs in germline DNA from peripheral blood lymphocytes may serve as risk factors for epithelial ovarian cancer (EOC). To reduce disease heterogeneity, we focused on the subset of cases with serous histology. The analysis was therefore based on 942 serous ovarian cancer patients and 1,682 healthy controls who were genotyped using the Illumina 610K quad array. Subjects with extreme noise and genomic waviness in log R ratio (LR) were excluded prior to segmentation; principal component analysis was performed to adjust for batch effects. CNV segmentation was performed on LR data from 22 autosomes using circular binary segmentation embedded in the Copy Number Analysis Module from Golden Helix SNP Variation Suite version 7. Copy number segment covariates were discretized based on the thresholds that signify a transition between copy number states (deletion/no deletion; duplication/no duplication) after the segmentation. Unconditional logistic regression on a log-additive model was used to evaluate the association between copy number states and serous EOC risk after adjusting for study sites. By comparing single marker copy number states at 388,958 SNPs on 22 autosomes, we observed a total of 134 SNPs significantly associated with risk of serous EOC with a p value below 10−6. Associations with deletion polymorphisms were observed on chromosomes 7, 8, 14, and 18 when controlling for false discovery rate at 1%; no duplication polymorphisms were significant. We observed a large deletion at chromosome 14 that occurred in 8.9% of cases but in only 3.9% of controls, with a p value of 5.59×10−8 (Odds Ratio (OR): 2.56, 95% confidence interval (CI): 1.82-3.60). Another common deletion on chromosome 7 occurred in 8.8% of cases and only 4.3% of controls (p=3.83×10−6; OR: 2.23, 95% CI: 1.60-3.10). Two additional regions on chromosomes 8 and 18 with deletion events less than 5% were also identified. Women who harbored the deletion on chromosome 8 were at lower risk of developing serous ovarian cancer (p=4.83×10−8; OR: 0.04, 95% CI: 0.01-0.30). Women who carried the deletion on chromosome 18 had an increased risk for serous EOC (p=9.04×10−7; OR: 7.26, 95% CI: 2.94-17.97). Further validation of these four regions using independent data sets is currently underway. In summary, this is the largest reported genome-wide study of CNVs and serous EOC risk. These preliminary results suggested that germline CNVs may play an important role in ovarian cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1649. doi:1538-7445.AM2012-1649

Abstract 2928: Functional effects of SNPs in non-coding RNAs at the 3q25 ovarian cancer susceptibility locus

Abstract Genome-wide association studies have identified six common, low penetrance susceptibility loci for epithelial ovarian cancer (EOC). The functional mechanisms underlying disease susceptibility at these loci are unknown. SNPs at the 3q25 locus confer a 1.2-fold risk of serous EOC (P=7.1x10-8). To identify causal SNP(s) we used the 1000 genomes project to identify 952 correlated SNPs within a 884kb linkage disequilibrium region. Of these, 786 tagging SNPs were genotyped in ∼20,000 invasive EOC cases and 20,000 controls. Fine mapping limited the size of the risk region to ∼130kb and 43 possible causal SNPs. This region contains four protein-coding genes; none of the 43 SNPs was predicted to have a functional effect on the translated protein. Genomic profiling data from The Cancer Genome Atlas analysis of ∼500 serous EOCs indicated one gene in the region (TIPARP) was significantly down regulated compared to normal tissues (P=0.005). Using RT-PCR expression analysis, we found significantly lower TIPARP expression in EOC cell lines (N=37) compared to normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cell lines (N=39) (P=1.57x10-8). TIPARP was also significantly downregulated in an in vitro model of early stage transformation of OSE cells (P=0.0003). Collectively, these data suggest that TIPARP is a novel tumor suppressor gene (TSG) in EOC development. TIPARP is a poly(ADP-ribose) polymerase known to catalyze histone ribosylation, an epigenetic modification that plays a role in DNA repair. We evaluated its functional significance in more detail using stable lentiviral-mediated shRNA knockdown of TIPARP in normal OSE/FTE cells. TIPARP knockdown induced cellular senescence similar to the effects of many classical TSG knockdowns in normal cells. We hypothesized that TIPARP may be involved in cellular response to DNA damage; when normal OSE/FTE cells were exposed to α-irradiation TIPARP was significantly upregulated in a dose-dependent manner. We examined the functional link between susceptibility SNPs and TiPARP expression. Of 43 putative causal SNPs, four fell within two non-coding RNAs- LOC730091 and TIPARP-AS1. There is no homology between LOC730091 and genes at the 3q25 locus; but TIPARP-ASI is a non-coding RNA with antisense sequence similarity to exon 1 of TIPARP. LOC730091 and TIPARP-AS1 were variably expressed in both normal ovarian and EOC cell lines. We found no correlation between LOC730091 and TIPARP expression; but cell lines expressing TIPARP-AS1 showed significantly reduced TIPARP expression. In summary, fine mapping at the 3q25 has identified multiple possible causal SNPs. Functional studies implicate TIPARP as a plausible target TSG in this region. EOC risk associated SNPs were located in a non-coding RNA that causes reduced expression of TIPARP suggesting a mechanism by which susceptibility SNPs may confer neoplastic transformation of ovarian epithelial cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2928. doi:1538-7445.AM2012-2928

Primary peritoneal and ovarian cancers: an epidemiological comparative analysis

We performed case–control analyses using data from the North Carolina Ovarian Cancer Study to determine risk factors that distinguish primary peritoneal cancer (PPC) from epithelial ovarian cancer (EOC). Our risk factor analyses were restricted to invasive serous cancers including 495 EOC cases, 62 PPC cases and 1,086 control women. Logistic regression analyses were used to calculate adjusted odds ratios and 95% confidence intervals for risk factor associations. Although many case–control associations for the invasive serous PPC cases were similar to those of the invasive serous EOC cases, some differences were observed including a twofold increase in risk of invasive serous PPC in women who were ≥35 years at last pregnancy, whereas a decreased risk was observed for invasive serous EOC risk. We could not confirm a previous report of an association between tubal ligation and PPC, a factor consistently associated with a decreased risk of EOC. The difference in the risk factor associations between invasive serous PPC and EOC cancers suggests divergent molecular development of peritoneal and ovarian cancers. A larger study to determine risk factors for invasive serous PPC is warranted.

P16(CDKN2) gene polymorphism: association with histologic subtypes of epithelial ovarian cancer in China

p16 is an important tumor suppressor gene, which is inactivated in many kinds of tumors. The common variants of p16 may be associated with the risk of certain tumors development. We analyzed the frequency of two adjacent polymorphisms in p16 exon 3 (540C-->G and 580C-->T) and their haplotype in blood samples from epithelial ovarian cancer (EOC) patients and healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The results showed that the genotype frequency of p16 580C-->T polymorphism was significantly different among histologic subtypes of EOC (P= 0.02). T allele carriers significantly reduced the risk of serous EOC; the adjusted odds ratio was 0.40 (95% CI = 0.19-0.84). There are neither association between p16 540C-->G polymorphism and EOC development, progression, nor association between the haplotypes of two single nucleotide polymorphisms and the tumor development. Our results suggested that the p16 580C-->T polymorphism might affect the individual susceptibility to specific subtypes of EOC. Different types of ovarian cancer might adopt distinct carcinogenetic pathways. However, this result may be further validated in a larger sample of patients.