Identification of DNA methylation based prognostic subtype and signature in epithelial ovarian cancer.

Background: Epithelial ovarian cancer (EOC) is a heterogeneous disease that exhibits different histological types, clinical characteristics, and molecular features. DNA methylation plays a crucial role in the development and progression of cancer and has been utilized for subtyping various tumors. This study focuses on classifying EOC based on DNA methylation and aims to characterize the disease through an integrated analysis of genomic, transcriptomic, and clinical data. Methods: Genome-wide DNA methylation profiling was performed on 137 EOC tumor tissues using Infinium MehylationEPIC array. Prognosis-related differentially methylated positions (DMPs) were identified through multivariate Cox proportional hazards regression models, and non-negative matrix factorization (NMF) approach was used to classify different subtypes. A prognosis prediction model was constructed using LASSO regression and nomogram was constructed. Results: Four methylation-based subtypes (MS1-MS4) were identified using 774 DMPs, showing significant differences in prognosis (P = 2.413 × 10-9).The MS1 group showed the best prognosis and the most favorable response to paclitaxel in combination with platinum-based chemotherapy. MS2 is characterized as an immune-excluded phenotype, while MS3 represents a metabolic subtype with a moderate prognosis as determined through differentially expressed genes and functional enrichment analysis. In contrast, MS4, recognized as a hypermethylated subtype, has the poorest prognosis and is marked by the highest methylation levels among the four subtypes. A four-DMP signature was developed to predict prognosis and methylation subtype, thereby enhancing clinical utility. Conclusion: Together, this study identified a novel molecular subtype of EOC, elucidating the heterogeneity of EOC from an epigenetic perspective and providinga new strategy for personalized treatment options for EOC patients. Citation Format: Wei Geng, Wei Liu, Lei Liu, Yuxin Chen, Dong Yang, Linqing Chai, Caiyun Huang, Lian Li. Identification of DNA methylation based prognostic subtype and signature in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5979.

Background: Epithelial ovarian cancer (EOC) is composed of five major histologic types: 1) high-grade serous carcinoma (HGSC), accounting for most cases (∼70%); and the rarer 2) clear cell, 3) endometrioid, 4) mucinous, and 5) low- grade serous carcinoma (LGSC). As EOC risk factors are histology specific, as are the site of precursor lesions, accurate subtyping is critical to understanding EOC prognostic factors and etiology. Our aim was to compare two currently employed histology assignment strategies using gene expression, DNA methylation, and clinical outcome data Methods: Histology assignment based on: a) pathologist, and b) an integrated pathologist and IHC prediction algorithm (pathIHC) (using ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1 staining patterns), was compared for tumors of all histologies at the Mayo Clinic, Rochester. The 500 most variable probes from Illumina Methylation450 BeadChips (N = 259) and Agilent 4×44K expression arrays (N = 245) were used to perform unsupervised hierarchical clustering. Fisher's Exact test was used to test the association of clusters with histology. Cox proportional hazards regression analysis was used to test the association of clusters and histology with time to progression (TTP) and time to death (TTD). Results: Eighty-two percent of tumors were concordant between histology assignment strategies. Clustering based on methylation data produced two distinct clusters. PathIHC produced more homogenous clusters (p-value = 2.8×10-16) than pathology alone (p = 1.3×10-9). Cluster M1, characterized by high levels of methylation across almost all probes, was enriched for the rarer EOC subtypes; cluster M2, characterized by moderate levels of methylation across 50%-75% of probes, was predominantly HGSC. These patterns were observed irrespective of histology assignment strategy; however, when using histology by pathologist, cluster M2 had more endometrioid and LGSC tumors interspersed with HGSC tumors. Clustering based on expression data also produced two clusters. PathIHC produced slightly more homogenous clusters (p = 9.0×10-11, pathology alone, p = 2.3×10-10). Cluster E1 was enriched for the rarer EOC subtypes; cluster E2 was primarily serous lineage tumours (HGSC and LGSC), particularly when using histology by pathIHC. Considering only clinical outcomes, histologies by pathology were more significantly different in terms of TTP (p = 1.1×10-6) and TTD (p = 1.7×10-3) than histologies by pathIHC (TTP, p = 5.4×10-6; TTD, p = 5.7×10-3). Conclusions: Histology by pathIHC produced more homogeneous clusters in both the methylation and expression data; thus, molecular data supports this strategy. Differences in clinical outcomes (TTP and TTD) between histology groups were more pronounced when using assignment by pathologist; thus, clinical data supports this strategy. Citation Format: M A. Earp, S J. Winham, S M. Armasu, B L. Fridley, M C. Larson, Z C. Fogarty, K R. Kalli, C Wang, G L. Keeney, J M. Cunningham, S Ramus, M Kobel, E L. Goode. Comparison of pathology versus IHC-based ovarian carcinoma histology assignment using gene expression, DNA methylation, and clinical outcome data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2015-4246

Background: Epithelial ovarian cancer (EOC), and other solid tumors, contain a variable proportion of tumors characterized by global DNA hypomethylation. This phenotype is known to involve loss of DNA methylation at repetitive elements (RE) and at single copy gene promoters, including cancer-germline (a.k.a. cancer-testis) antigen genes. Global DNA hypomethylation in EOC coincides with tumor progression and reduced survival in EOC patients. Despite the clinical importance of global DNA hypomethylation, we currently have a limited understanding of the origin, the targets, and the consequences of this EOC phenotype. Objectives: The purpose of this study was to: i) examine global gene expression in globally hypomethylated EOC, ii) to identify the molecular pathways deregulated in these tumors, iii) to discover and validate novel and clinically relevant targets of DNA hypomethylation in EOC, iv) to conduct DNA methylome analysis to more precisely define the genomic locations effected by global DNA hypomethylation in EOC, and v) to determine whether global DNA hypomethylation impact RE gene expression in EOC. Methods: Global methylation status in EOC was determined using quantitative bisulfite pyrosequencing of the LINE1 RE. Affymetrix microarrays, RT-qPCR, and total RNAseq were used to measure gene expression in normal ovary (NO), LINE1 hypomethylated EOC, and LINE1 hypermethylated (i.e. normally methylated) EOC. Pathway analysis was conducted on differentially expressed genes (DEG) between NO and EOC and between the two EOC groups. Illumina Infinium 450K arrays and Agilent Sure Select methyl-seq were used to examine the DNA methylome of NO and EOC. Quantitative sodium bisulfite pyrosequencing was used to determine locus-specific DNA methylation in NO and EOC. Results: Global mRNA expression was distinct in LINE1 hypomethylated EOC, with ~70% of DEG upregulated, implicating DNA hypomethylation in gene activation. The most significantly altered pathway in LINE1 hypomethylated EOC was cell cycle, implicating enhanced proliferation in this phenotype. Cancer germline genes not previously known to be regulated by DNA methylation in EOC, including CT45 and PRAME, were identified and characterized. DNA methylome analysis of LINE1 hypomethylated EOC indicated that hypomethylation is not evenly dispersed across the genome, but rather is regionally localized, including at nuclear lamina associated domains (LAD). Preliminary analysis of RNAseq data indicated that specific RE are overexpressed in LINE1 hypomethylated tumors. Conclusions: Pathway analysis suggests that rapid cellular proliferation coupled with inherent inefficiencies of maintenance DNA methylation at specific genomic locations may contribute to global DNA hypomethylation in EOC. DNA hypomethylation is linked to gene activation in EOC, and important targets of this defect are cancer germline genes, which are likely to contribute to oncogenesis but may also be targeted by immunotherapy. Global DNA hypomethylation appears to be concentrated at specific genomic locations including LADs, and is connected not only to RE hypomethylation, but also to enhanced RE expression. Higher-order nuclear changes and enhanced RE expression are potential mechanisms driving genomic instability and/or poor prognosis in EOC patients displaying global DNA hypomethylation. Citation Format: Wa Zhang, David Klinkebiel, Sanjit Pandey, Dan Wang, Song Liu, Chittibabu Guda, Kunle Odunsi, Adam R. Karpf. Genomic and epigenomic characterization of global DNA hypomethylation in human epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B12.

Background Epithelial ovarian cancer (EOC) is an extremely lethal gynecological malignancy and has the potential to benefit from the immune checkpoint blockade (ICB) therapy, whose efficacy highly depends on the complex tumor microenvironment (TME). Method and Result We comprehensively analyze the landscape of TME and its prognostic value through immune infiltration analysis, somatic mutation analysis, and survival analysis. The results showed that high infiltration of immune cells predicts favorable clinical outcomes in EOC. Then, the detailed TME landscape of the EOC had been investigated through “xCell” algorithm, Gene set variation analysis (GSVA), cytokines expression analysis, and correlation analysis. It is observed that EOC patients with high infiltrating immune cells have an antitumor phenotype and are highly correlated with immune checkpoints. We further found that dendritic cells (DCs) may play a dominant role in promoting the infiltration of immune cells into TME and forming an antitumor immune phenotype. Finally, we conducted machine-learning Lasso regression, support vector machines (SVMs), and random forest, identifying six DC-related prognostic genes (CXCL9, VSIG4, ALOX5AP, TGFBI, UBD, and CXCL11). And DC-related risk stratify model had been well established and validated. Conclusion High infiltration of immune cells predicted a better outcome and an antitumor phenotype in EOC, and the DCs might play a dominant role in the initiation of antitumor immune cells. The well-established risk model can be used for prognostic prediction in EOC.

Advances in Nonnegative Matrix and Tensor Factorization

Colorectal cancer is the third most common cancer in Australia and is responsible for the death of over four thousand Australians each year. There are two overarching molecular pathways leading to colorectal cancer. The conventional pathway, which is responsible for ~75% of colorectal cancer diagnoses, occurs in a step-wise manner and is the consequence of a series of genetic alterations including mutations of tumour suppressor genes and gross chromosomal abnormalities. This pathway has been extensively studied over the past three decades.The serrated neoplasia pathway is responsible for the remaining colorectal cancers. This pathway is triggered by oncogenic BRAF mutation and these cancers accumulate epigenetic alterations while progressing to invasive cancer. DNA methylation is important in serrated neoplasia, however the extent and role of DNA methylation on the initiation and progression of serrated lesions is not clear. DNA methylation accumulates in tissues with age, and advanced serrated lesions and cancers occur almost exclusively in elderly patients. How this methylation affects serrated lesions is unknown. In this thesis I set out to address three key research questions related to DNA methylation, age and serrated colorectal neoplasia. First, what is the extent of DNA methylation in colorectal cancers?; Second, Does age-related hypermethylation, and namely that occurring at the loci encoding tumour suppressor genes, increase the risk of serrated colorectal neoplasia?; and if true, how can we reconcile this with the existence of early onset serrated colorectal cancer?In the first chapter of this thesis, I examine the DNA methylation and transcriptional architecture of 216 colorectal cancer samples collected consecutively at the Royal Brisbane and Women’s hospital. Clustering analysis of DNA methylation data revealed five distinct subtypes of colorectal cancers, including two clusters with high levels of DNA methylation, two with intermediate levels of DNA methylation, and one devoid of DNA methylation alterations. This study highlighted striking associations between DNA methylation and age, gender and tumour location. Oncogenic BRAF mutations were common in CIMP-H1, but rare in CIMP-H2. The inverse was true for CIMP-H2. These analyses were robustly verified using data from TCGA. Using exome capture sequencing data from TCGA, we assessed the frequency of mutations in genes encoding epigenetic regulators in cancers by methylation subtype. The frequency of mutation in epigenetic regulators increased concomitant with increasing genomic hypermethylation, and the spectrum of mutations differed by methylation subtype. Mutations in epigenetic regulators may provide insight into the epigenetic aberrancies observed in these highly methylated cancers.In the second chapter of this thesis, I investigate the role of age and age-associated DNA methylation and the associated transcriptional changes, in the risk of serrated neoplastic transformation using a murine model of serrated neoplasia driven by oncogenic Braf. First, the DNA methylation landscape of wild type animals was assessed over the lifespan of the animals via reduced representation bisulphite sequencing. This revealed pervasive age-associated DNA methylation, with a tendency for methylation to accumulate at the promoters of genes encoding WNT signalling regulators. Activating the Braf oncogene at wean induces a remarkable acceleration of DNA methylation accumulation, with a stronger still enrichment at WNT signalling loci. Lastly, we activated the Braf mutation in mice at wean for five months, and at nine months of age for the same period. We observe a 10.5 fold relative risk of advanced serrated lesions in animals induced at nine months compared with the younger animals, despite the same period of oncogenic exposure. These data directly implicate the aging process in determining the malignant threat of Braf induced neoplasia. Methylation analysis of these animals revealed differences in loci identified as age-associated, and those accelerated by oncogenic Braf. This study strongly implicates age and DNA methylation as a risk factors for serrated neoplastic progression and may have implications for patient surveillance.In the third chapter of this thesis, I attempt to elucidate the role of mutations in WNT signalling genes in serrated colorectal cancers, hypothesising that genetic alterations of WNT regulators will underpin early onset BRAF mutant cancers. Large exome sequencing data sets from earlier studies were collated to establish a cohort of 199 BRAF mutant colorectal cancers with somatic mutation data. This study reveals a mosaic of WNT pathway mutations, including several potential novel driver genes. APC mutations in the setting of BRAF mutant cancers were associated with poor patient outcome, and importantly, younger age at diagnosis. These data indicates that mutation of APC could provide an alternate avenue for progressing to invasive cancer, abrogating the need for excessive DNA methylation alterations.To conclude, this thesis has comprehensively evaluated the role of DNA methylation and age in the risk of serrated colorectal neoplasia. These data improve our understanding of the role of DNA methylation in colorectal carcinogenesis and may provide an impetus for investigating patient-centric surveillance regimens according to the age of patients at index colonoscopy.

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy, accounting for over 200,000 deaths worldwide per year. EOC is a highly heterogeneous disease, classified into five major histological subtypes-high-grade serous (HGSOC), clear cell (CCOC), endometrioid (ENOC), mucinous (MOC) and low-grade serous (LGSOC) ovarian carcinomas. Classification of EOCs is clinically beneficial, as the various subtypes respond differently to chemotherapy and have distinct prognoses. Cell lines are often used as in vitro models for cancer, allowing researchers to explore pathophysiology in a relatively cheap and easy to manipulate system. However, most studies that make use of EOC cell lines fail to recognize the importance of subtype. Furthermore, the similarity of cell lines to their cognate primary tumors is often ignored. Identification of cell lines with high molecular similarity to primary tumors is needed in order to better guide pre-clinical EOC research and to improve development of targeted therapeutics and diagnostics for each distinctive subtype. This study aims to generate a reference dataset of cell lines representative of the major EOC subtypes. We found that non-negative matrix factorization (NMF) optimally clustered fifty-six cell lines into five groups, putatively corresponding to each of the five EOC subtypes. These clusters validated previous histological groupings, while also classifying other previously unannotated cell lines. We analysed the mutational and copy number landscapes of these lines to investigate whether they harboured the characteristic genomic alterations of each subtype. Finally we compared the gene expression profiles of cell lines with 93 primary tumor samples stratified by subtype, to identify lines with the highest molecular similarity to HGSOC, CCOC, ENOC, and MOC. In summary, we examined the molecular features of both EOC cell lines and primary tumors of multiple subtypes. We recommend a reference set of cell lines most suited to represent four different subtypes of EOC for both in silico and in vitro studies. We also identify lines displaying poor overall molecular similarity to EOC tumors, which we argue should be avoided in pre-clinical studies. Ultimately, our work emphasizes the importance of choosing suitable cell line models to maximise clinical relevance of experiments.

<div>Abstract<p><b>Purpose:</b> The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.</p><p><b>Experimental Design:</b> We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated <i>in vitro</i> with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC.</p><p><b>Results:</b> Compared with normal ovary, bulk EOC tissues display increased <i>NY-ESO-1</i> expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, <i>NY-ESO-1</i> expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines.</p><p><b>Conclusion:</b> DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.</p></div>

The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC. We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated in vitro with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC. Compared with normal ovary, bulk EOC tissues display increased NY-ESO-1 expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, NY-ESO-1 expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines. DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.

<div>Abstract<p><b>Purpose:</b> The cancer/germline antigen NY-ESO-1 is variably expressed in epithelial ovarian cancer (EOC), with most tumors showing low or heterogeneous expression, which limits patient responses to NY-ESO-1 vaccine therapy. We tested the hypothesis that promoter and global genomic DNA methylation status correlates with intertumor and intratumor NY-ESO-1 expression status in EOC.</p><p><b>Experimental Design:</b> We utilized 78 EOC tumors and 10 normal ovary controls for quantitative DNA methylation analyses and NY-ESO-1 expression analysis by immunohistochemistry (IHC) and quantitative reverse transcriptase PCR. A subset of EOC tumors were used to perform microdissections of NY-ESO-1 IHC-positive and NY-ESO-1 IHC-negative tissue regions, followed by DNA methylation analyses. EOC cell lines were treated <i>in vitro</i> with decitabine to determine the functional contribution of DNA methylation to NY-ESO-1 gene regulation in EOC.</p><p><b>Results:</b> Compared with normal ovary, bulk EOC tissues display increased <i>NY-ESO-1</i> expression, reduced NY-ESO-1 promoter methylation, and reduced LINE-1 DNA methylation. However, <i>NY-ESO-1</i> expression is not significantly associated with NY-ESO-1 promoter methylation status in bulk tumors. We hypothesized that this resulted from heterogeneous intratumor NY-ESO-1 expression. Supporting this idea, experiments using microdissected material revealed that intertumor and intratumor NY-ESO-1 expression heterogeneity is significantly correlated with promoter and global DNA methylation status in EOC. Moreover, decitabine treatment functionally restored NY-ESO-1 expression in nonexpressing EOC cell lines.</p><p><b>Conclusion:</b> DNA methylation status is associated with both intertumor and intratumor NY-ESO-1 expression status in EOC. These findings support a novel chemoimmunotherapy approach using decitabine to augment NY-ESO-1 vaccine therapy for treatment of recurrent EOC.</p></div>

Background: Prostate-, Ovary-, Testis-, and Placenta-Expressed Gene (POTE) is a recently discovered gene family consisting of 12 autosomal and pericentromeric-located cancer germline/cancer-testis antigen genes. POTE genes have been reported to be expressed in many solid tumor malignancies, and recent data suggest that POTE proteins may be viable targets for cancer immunotherapy. DNA methylation changes are common in epithelial ovarian cancer (EOC), and these changes include DNA hypomethylation at specific repetitive elements (RE), including the interspersed retrotransposon LINE1, and at pericentromeric repeats. Objective: The purpose of this study was to determine the expression of POTE genes in EOC, to assess whether DNA methylation changes and/or other epigenetic mechanisms regulate POTE expression in EOC, and to define the potential functional contribution(s) of POTE expression to this disease. Methods: Affymetrix microarrays and RT-qPCR were used to determine POTE gene expression in human normal ovary (NO) and EOC tumors. The DNA methylation status of POTE genes and neighboring pericentromeric regions were determined using sodium bisulfite clonal sequencing and quantitative bisulfite pyrosequencing. The impact of epigenetic drug treatment on POTE gene expression in EOC cell lines was determined. POTE gene knockdown in EOC cell lines was accomplished using RNA interference, and POTED was overexpressed in EOC cell lines and immortalized ovarian surface epithelial (IOSE) cells. Cell proliferation, apoptosis, cell migration, and cell invasion were determined following POTE knockdown or overexpression in cell lines. Results: Widespread activation of POTE gene expression occurred in EOC, as compared to NO. POTE gene expression levels were significantly higher in EOC tumors showing LINE1 hypomethylation, as compared to EOC tumors showing normal LINE1 methylation, linking global DNA methylation status to POTE gene expression. Hypomethylation of pericentromeric DNA, as determined using NBL2 pyrosequencing, was also linked to POTE expression and hypomethylation. POTE mRNA and protein expression was induced by treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors. POTE gene knockdown in EOC cell lines had a small impact on cell proliferation and apoptosis, but resulted in significantly reduced cell migration and cell invasion. POTED overexpression experiments are currently in progress. Conclusions: POTE genes are widely expressed in EOC, and expression is significantly increased in tumors displaying global DNA hypomethylation. Additional evidence for epigenetic regulation of POTE genes is their induction following treatment with epigenetic modulatory drugs. POTE gene expression in cancer may closely relate to the epigenetic status of pericentromeric DNA. Importantly, POTE proteins appear to functionally contribute to EOC, by promoting cell migration and invasion. Based on these data, further analysis of POTE gene regulation and function in EOC, and development of POTE targeted therapeutic approaches, is warranted. Citation Format: Ashok Sharma, Wa Zhang, Smitha James, Christina Kufel, David Klinkebiel, Kunle Odunsi, Adam R. Karpf. POTE gene expression, epigenetic regulation, and oncogenic functions in human epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B80.

Bayesian Estimators are very useful in speech enhancement and noise reduction. But, it is noted that the traditional estimators process only amplitudes and the phase is left unprocessed. Among the Bayesian estimators, Super- Gaussian based estimators provide improved noise reduction. Super-Gaussian Bayesian estimators, which uses processed phase information for estimation of amplitudes provides further improved results. In this work, the Complex speech coefficients given Uncertain Phase (CUP) based Bayesian estimators like CUP-GG (CUP Estimator with speech spectral coefficients assumed as Gamma and noise spectral coefficients as Generalized Gamma), CUP-NG (Speech as Nakagami) are compared under white noise, pink noise, Babble noise and Non-Stationary factory noise conditions. The statistical estimators show less effective results under completely non-stationary assumptions like non-stationary factory noise, babble noise etc. Non-negative Matrix Factorization (NMF) based algorithms show better performance for non stationary noises. The drawback of NMF is, it requires apriori knowledge about speech. This drawback can be overcome by taking the advantages of both statistical approaches and NMF approaches. NR-NMF and WR-NMF speech enhancement methods are developed by providing posteriori regularization based on statistical assumption of speech and noise DFT coefficients distribution. Also a speech enhancement method which uses CUP-GG estimator and NMF with online noise bases update are considered for comparison. The progress in neural network based approaches for speech enhancement further shown that with large dataset and better training, the speech enhancement algorithms results in improved results. In this work, the neural network approach for speech enhancement is implemented and compared the method with traditional estimators and NMF approaches. For generalization of unseen noise types the proposed neural network approach uses dropout. Also for training the network, the features obtained from apriori SNR and aposteriori SNR is used in this method. The objective of this paper is to analyze the performance of speech enhancement methods based on Neural Network, NMF and statistical based. The objective performance measures Perceptual Evaluation of Speech Quality (PESQ), Short-Time Objective Intelligibility (STOI), Signal to Noise Ratio (SNR), Segmental SNR (Seg SNR) are considered for comparison.

Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1-2.8) but not mucinous tumors (1.1; 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer.

LINE1 and Alu repetitive element DNA methylation in tumors and white blood cells from epithelial ovarian cancer patients

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recently reported a reduction in the average overall mortality among ovarian cancer patients screened with an annual sequential, multimodal strategy that tracked biomarker CA125 over time, where increasing serum CA125 levels prompted ultrasound. However, multiple cases were documented wherein serum CA125 levels were rising, but ultrasound screens were normal, thus delaying surgical intervention. A significant factor which could contribute to false negatives is that many aggressive ovarian cancers are believed to arise from epithelial cells on the fimbriae of the fallopian tubes, which are not readily imaged. Moreover, because only a fraction of metastatic tumors may reach a sonographically-detectable size before they metastasize, annual screening with ultrasound may fail to detect a large fraction of early-stage ovarian cancers. The ability to detect ovarian carcinomas before they metastasize is critical and future efforts towards improving screening should focus on identifying unique features specific to aggressive, early-stage tumors, as well as improving imaging sensitivity to allow for detection of tubal lesions. Implementation of a three-stage multimodal screening strategy in which a third modality is employed in cases where the first-line blood-based assay is positive and the second-line ultrasound exam is negative may also prove fruitful in detecting early-stage cases missed by ultrasound.