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14. Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Author

Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D, Butzow, Ralf, Campbell, Ian G, Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S, Cramer, Daniel W, deFazio, Anna, Dennis, Joe, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Edwards, Digna Velez, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Giles, Graham G, Glasspool, Rosalind M, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Heitz, Florian, Hildebrandt, Michelle A, Høgdall, Estrid, Høgdall, Claus K, Huntsman, David G, Kar, Siddhartha P, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Koushik, Anita, Lambrechts, Diether, Le, Nhu D, Levine, Douglas A, Massuger, Leon F, Matsuo, Keitaro, May, Taymaa, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N, Moorman, Patricia G, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Olsson, Håkan, Onland-Moret, N Charlotte, Park, Sue K, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Phelan, Catherine M, Pike, Malcolm C, Ramus, Susan J, Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, Veronica W, Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J, Sutphen, Rebecca, Swerdlow, Anthony J, Szafron, Lukasz M, Teo, Soo Hwang, Tworoger, Shelley S, Tyrer, Jonathan P, Webb, Penelope M, Wentzensen, Nicolas, White, Emily, Willett, Walter C, Wolk, Alicja, Woo, Yin Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul DP, Zheng, Wei, and Long, Jirong

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Rare Diseases, Ovarian Cancer, Cancer Genomics, Prevention, Women's Health, Cancer, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Cohort Studies, DNA Methylation, Female, Genetic Predisposition to Disease, Humans, Models, Genetic, Ovarian Neoplasms, Predictive Value of Tests, Risk, White People, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
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 × 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.

Published
2019

18. A systematic review of simulation training for lower extremity bypass procedures.

Author

Siddiqui, Nadeem Ahmed, Javed, Aden, and Pirzada, Ammar

Abstract

Objectives: Simulation is used across surgical specialties for skill enhancement. The choice and assessment method of a simulator varies across literature. In the age of endovascular approach, trainees have limited exposure to open lower limb bypass procedures which needs attention. This review aims to assess the utility of simulation training in lower limb bypass surgery using Kirkpatrick's model. Methods: Using PRISMA statement, we included all the studies done on simulators in lower limb bypass surgical procedures for this systematic review. The primary outcome was to assess the effectiveness of different types of simulation used for lower limb bypass surgery using the Kirkpatrick's model for training evaluation. Results: An initial search identified 295 articles out of which 7 articles were found to be eligible for this systematic review. A variety of simulators were used including cadavers and synthetic models. Most studies (n =5) found the use of simulation as an effective tool in achieving technical competence. All the five studies we found at level 2 on Kirpatrick's model evaluation. Conclusion: Most of the existing studies are at level 2 of Kirkpatrick's model which reflects learning changes in trainees after simulation. Feedback mechanism needs to be evolved where the improvement after simulation training can be gauged by its replication in clinical practice and improved patient care practices corresponding to the highest level of Kirkpatrick's model. [ABSTRACT FROM AUTHOR]

Published
2024
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19. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Author

Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Vestrheim Thomsen, Liv Cecilie, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen

Subjects
Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
Abstract

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Published
2018

20. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author

Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Women's Health, Cancer, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Body Height, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Geography, Humans, Mendelian Randomization Analysis, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Published
2018

27. List of contributors

Author

Agnihotri, Nidhi, primary, Anantharaj, R., additional, Anju, K.A., additional, Annal, Umaiyambika Neduvel, additional, Badgujar, Kirtikumar C., additional, Badgujar, Vivek C., additional, Bhakthochidan, Sholinghur Asuri, additional, Bhanage, Bhalchandra M., additional, Boobalan, Maria Susai, additional, Cherian, Elsa, additional, Chozhavendhan, S., additional, Dey, Pinaki, additional, Dey, Pritam, additional, Dhakal, Bijay, additional, Dhithya, V., additional, Dilip, Kevin Joseph, additional, Divakar, K., additional, Gebeyehu, Kaleab Bizuneh, additional, George, Jenet, additional, Gill, Manjot, additional, Gnana Prakash, D., additional, Gnansounou, Edgard, additional, Gomathi, K., additional, Gopalakrishnan, B., additional, Gopinath, M., additional, Gunturu, Bhargavi, additional, Gupta, Geetika, additional, Gurunathan, Baskar, additional, Hameed, Adam Shahul, additional, Han, Jeehoon, additional, Iyyappan, J., additional, Jacob, Samuel, additional, Jayakumar, Mani, additional, Kalavathy, G., additional, Kanishka, V., additional, Karmegam, Natchimuthu, additional, Karthikadevi, S., additional, Karuppasamy, Ilango, additional, Kaviprabha, A., additional, Kheerthivasan, R., additional, Krishnan, Chandraraj, additional, Kumar, Amit, additional, Kuppusamy Vaithilingam, Selvakumar, additional, Kurian, Vinoj, additional, Kusumaningtyas, Ratna Dewi, additional, Mahmudati, Ririn, additional, Mandade, Prasad, additional, Mani, Vijay, additional, Masakapalli, Shyam Kumar, additional, Meramo, Samir, additional, Mishra, Bishwambhar, additional, Mohan, Lakshmi, additional, Mohanty, Upasana, additional, Mondal, Monoj Kumar, additional, Muthu Kumara Pandian, A., additional, Nagarajan, Praveena, additional, Nakkeeran, E., additional, Natarajan, Arunodhaya, additional, Nayak, Jayato, additional, Nimdeo, Yogesh M., additional, Nirmal, Louis Anto, additional, Pandey, Ashok, additional, Pandian, Sivakumar, additional, Ponnusamy, Senthil Kumar, additional, Prasetiawan, Haniif, additional, Prathiba, S., additional, Priyanka, A., additional, Purnamasari, Indah, additional, Radhika, G.B., additional, Rajagopalan, Gobinath, additional, Rajamehala, M., additional, Rajasri, Y., additional, Rajendran, Naveenkumar, additional, Ramakrishnan, Geethalakshmi, additional, Ramesh, P., additional, Ranganathan, Panneerselvam, additional, Rathankumar, Abiram Karanam, additional, Ray, Srimanta, additional, Reddy, C. Nagendranatha, additional, Roshini, Veeraraghavan Babulu, additional, Sahadevan, Renganathan, additional, Saikia, Kongkona, additional, Saranya, P., additional, Saravanan, Priyanka, additional, Shaji, Anna, additional, Shalini, A., additional, Siddiqui, Nadeem, additional, Srinivas, G., additional, Srinivas, T., additional, Su, Renugaa, additional, Swapna, V., additional, Thakur, Jyotika, additional, Vaidyanathan, Vinoth Kumar, additional, Vaishnavi, A., additional, Vichitra, M., additional, Vijay Pradhap Singh, M., additional, Vineetha, Y., additional, Vishal, Ravichandran, additional, Wasewar, Kailas L., additional, and Yuvanashree, E., additional

Published
2022
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29. Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Author

Dicks, Ed, Song, Honglin, Ramus, Susan J, Van Oudenhove, Elke, Tyrer, Jonathan P, Intermaggio, Maria P, Kar, Siddhartha, Harrington, Patricia, Bowtell, David D, Group, AOCS Study, Cicek, Mine S, Cunningham, Julie M, Fridley, Brooke L, Alsop, Jennifer, Jimenez-Linan, Mercedes, Piskorz, Anna, Goranova, Teodora, Kent, Emma, Siddiqui, Nadeem, Paul, James, Crawford, Robin, Poblete, Samantha, Lele, Shashi, Sucheston-Campbell, Lara, Moysich, Kirsten B, Sieh, Weiva, McGuire, Valerie, Lester, Jenny, Odunsi, Kunle, Whittemore, Alice S, Bogdanova, Natalia, Dürst, Matthias, Hillemanns, Peter, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Tischkowitz, Marc, Levine, Douglas, Brenton, James D, Dörk, Thilo, Goode, Ellen L, Gayther, Simon A, and Pharoah, Paul DP

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Genetic Testing, Rare Diseases, Ovarian Cancer, Clinical Research, Cancer, Prevention, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, ovarian cancer, susceptibility genes, DNA repair, next generation sequencing, Next generation sequencing, Susceptibility Genes, Oncology and carcinogenesis
Abstract

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8x10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Published
2017

30. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival

Author

Sucheston-Campbell, Lara E, Cannioto, Rikki, Clay, Alyssa I, Etter, John Lewis, Eng, Kevin H, Liu, Song, Battaglia, Sebastiano, Hu, Qiang, Szender, J Brian, Minlikeeva, Albina, Joseph, Janine M, Mayor, Paul, Abrams, Scott I, Segal, Brahm H, Wallace, Paul K, Soh, Kah Teong, Zsiros, Emese, Anton-Culver, Hoda, Bandera, Elisa V, Beckmann, Matthias W, Berchuck, Andrew, Bjorge, Line, Bruegl, Amanda, Campbell, Ian G, Campbell, Shawn Patrice, Chenevix-Trench, Georgia, Study, on behalf of the Australian Ovarian Cancer, Cramer, Daniel W, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Diergaarde, Brenda, Doerk, Thilo, Doherty, Jennifer A, du Bois, Andreas, Eccles, Diana, Engelholm, Svend Aage, Fasching, Peter A, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind M, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemmanns, Peter, Høgdall, Claus, Høgdall, Estrid VS, Huzarski, Tomasz, Jensen, Allan, Johnatty, Sharon E, Jung, Audrey, Karlan, Beth Y, Klapdor, Reudiger, Kluz, Tomasz, Konopka, Bożena, Kjær, Susanne Krüger, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lester, Jenny, Lubiński, Jan, Levine, Douglas A, Lundvall, Lene, McGuire, Valerie, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Ness, Roberta B, Orsulic, Sandra, Paul, James, Pearce, Celeste Leigh, Pejovic, Tanja, Pharoah, Paul, Ramus, Susan J, Rothstein, Joseph, Rossing, Mary Anne, Rübner, Matthias, Schildkraut, Joellen M, Schmalfeldt, Barbara, Schwaab, Ira, Siddiqui, Nadeem, Sieh, Weiva, Sobiczewski, Piotr, Song, Honglin, Terry, Kathryn L, Van Nieuwenhuysen, Els, Vanderstichele, Adriaan, Vergote, Ignace, Walsh, Christine S, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wu, Anna H, Ziogas, Argyrios, Odunsi, Kunle, Chang-Claude, Jenny, Goode, Ellen L, and Moysich, Kirsten B

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Cancer, Ovarian Cancer, Rare Diseases, Prevention, Genetics, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Genetic Variation, Humans, Myeloid-Derived Suppressor Cells, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Australian Ovarian Cancer Study, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

Published
2017

32. British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: Recommendations for practice

Author

Reed, Nick, Balega, Janos, Barwick, Tara, Buckley, Lynn, Burton, Kevin, Eminowicz, Gemma, Forrest, Jenny, Ganesan, Raji, Harrand, Rosie, Holland, Cathrine, Howe, Tamara, Ind, Thomas, Iyer, Rema, Kaushik, Sonali, Music, Robert, Sadozye, Azmat, Shanbhag, Smruta, Siddiqui, Nadeem, Syed, Sheeba, Percival, Natalie, Whitham, Natasha Lauren, Nordin, Andy, and Fotopoulou, Christina

Published
2021
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37. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

Author

French, Juliet D, Johnatty, Sharon E, Lu, Yi, Beesley, Jonathan, Gao, Bo, Kalimutho, Murugan, Henderson, Michelle J, Russell, Amanda J, Kar, Siddhartha, Chen, Xiaoqing, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, O’Reilly, Martin, Wang, Chen, Korbie, Darren J, Group, Australian Ovarian Cancer Study, Study, Australian Cancer, Lambrechts, Diether, Despierre, Evelyn, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Pisterer, Jacobus, Hillemanns, Peter, Nakanishi, Toru, Yatabe, Yasushi, Goodman, Marc T, Lurie, Galina, Matsuno, Rayna K, Thompson, Pamela J, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James M, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen M, Iversen, Ed, Weber, Rachel Palmieri, Brennan, Donal, Berchuck, Andrew, Pharoah, Paul, Harnett, Paul, Norris, Murray D, Haber, Michelle, Goode, Ellen L, Lee, Jason S, Khanna, Kum Kum, Meyer, Kerstin B, Chenevix-Trench, Georgia, deFazio, Anna, Edwards, Stacey L, MacGregor, Stuart, and Consortium, on behalf of the Ovarian Cancer Association

Subjects
Genetics, Rare Diseases, Human Genome, Ovarian Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Cohort Studies, Cystadenocarcinoma, Serous, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Fallopian Tube Neoplasms, Female, Follow-Up Studies, Germ-Line Mutation, Humans, Ovarian Neoplasms, Peritoneal Neoplasms, Polymorphism, Single Nucleotide, Prognosis, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Transcription Factors, Tumor Cells, Cultured, epithelial ovarian cancer, progression free survival, genome-wide association study, PSIP1, chromosome conformation capture, Australian Ovarian Cancer Study Group, Australian Ovarian Cancer Study, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis
Abstract

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.

Published
2016

39. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author

Johnatty, Sharon E, Group, on behalf of the Australian Ovarian Cancer Study, Tyrer, Jonathan P, Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Levine, Douglas A, Kiemeney, Lambertus A, Massuger, Leon FAG, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S, McGuire, Valerie, Rothstein, Joseph H, Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O, Wu, Anna H, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K, Spiewankiewicz, Beata, Goodman, Marc T, Wilkens, Lynne R, Carney, Michael E, Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Group, on behalf of the AGO Study, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C, Fogarty, Zachary C, Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L, Cunningham, Julie M, Vierkant, Robert A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, and Pharoah, Paul DP

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Genetics, Human Genome, Precision Medicine, Rare Diseases, Women's Health, Cancer Genomics, Ovarian Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Alleles, Carcinoma, Ovarian Epithelial, Computational Biology, Female, Genome-Wide Association Study, Genotype, Humans, Kaplan-Meier Estimate, Meta-Analysis as Topic, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, AGO Study Group, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeChemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental designWe analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.ResultsFive SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).ConclusionsWe have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.

Published
2015

40. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

Author

Kelemen, Linda E, Terry, Kathryn L, Goodman, Marc T, Webb, Penelope M, Bandera, Elisa V, McGuire, Valerie, Rossing, Mary Anne, Wang, Qinggang, Dicks, Ed, Tyrer, Jonathan P, Song, Honglin, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Timorek, Agnieszka, Menon, Usha, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Narod, Steven A, Risch, Harvey A, McLaughlin, John R, Siddiqui, Nadeem, Glasspool, Rosalind, Paul, James, Carty, Karen, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Kiemeney, Lambertus A, Massuger, Leon FAG, van Altena, Anne M, Aben, Katja KH, Olson, Sara H, Orlow, Irene, Cramer, Daniel W, Levine, Douglas A, Bisogna, Maria, Giles, Graham G, Southey, Melissa C, Bruinsma, Fiona, Kjaer, Susanne K, Høgdall, Estrid, Jensen, Allan, Høgdall, Claus K, Lundvall, Lene, Engelholm, Svend-Aage, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Thompson, Pamela J, Lurie, Galina, Wilkens, Lynne R, Lambrechts, Diether, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Beesley, Jonathan, AOCS Study Group/ACS Investigators, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Doherty, Jennifer A, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel, Chang-Claude, Jenny, Rudolph, Anja, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Bogdanova, Natalia, Antonenkova, Natalia, Odunsi, Kunle, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Ness, Roberta B, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Wu, Xifeng, Lu, Karen, Liang, Dong, Hildebrandt, Michelle AT, Weber, Rachel Palmieri, and Iversen, Edwin S

Subjects
AOCS Study Group/ACS Investigators, Humans, Carcinoma, Ovarian Neoplasms, Folic Acid Deficiency, Genetic Predisposition to Disease, Folic Acid, Dihydrouracil Dehydrogenase (NADP), Neoplasm Proteins, Diet, Multivariate Analysis, Risk Factors, Case-Control Studies, Energy Intake, Polymorphism, Single Nucleotide, Dietary Supplements, European Continental Ancestry Group, Female, Genome-Wide Association Study, Global Health, Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1, Rare Diseases, Cancer, Ovarian Cancer, Genetics, Nutrition, 2.1 Biological and endogenous factors, Nutrition & Dietetics, Food Science, Food Sciences, Nutrition and Dietetics, Public Health and Health Services
Abstract

ScopeWe reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

41. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

Author

Hedditch, Ellen L, Gao, Bo, Russell, Amanda J, Lu, Yi, Emmanuel, Catherine, Beesley, Jonathan, Johnatty, Sharon E, Chen, Xiaoqing, Harnett, Paul, George, Joshy, Australian Ovarian Cancer Study Group, Williams, Rebekka T, Flemming, Claudia, Lambrechts, Diether, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Nakanishi, Toru, Yatabe, Yasushi, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susan K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen, Iversen, Ed, Weber, Rachel P, Berchuck, Andrew, Goode, Ellen, Bowtell, David D, Chenevix-Trench, Georgia, deFazio, Anna, Norris, Murray D, MacGregor, Stuart, Haber, Michelle, and Henderson, Michelle J

Subjects
Australian Ovarian Cancer Study Group, Humans, Neoplasms, Glandular and Epithelial, Cystadenocarcinoma, Serous, Ovarian Neoplasms, ATP-Binding Cassette Transporters, RNA, Messenger, Cell Movement, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Female, Neoplastic Stem Cells, Genome-Wide Association Study, Kaplan-Meier Estimate, Real-Time Polymerase Chain Reaction, Neoplasm Grading, ATP Binding Cassette Transporter 1, Carcinoma, Ovarian Epithelial, Ovarian Cancer, Rare Diseases, Biotechnology, Genetics, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Published
2014

43. Conceptual and molecular docking study of newly developed antiepileptic drug cenobamate

Author

Anam Ilyas, Shagufi Nazar, Siddiqui, Nadeem, Ozair Alam, M Shaharyar, and Shaiza Siddiqui

Subjects
Cenobamate, Tetrazole derivative, Focal-onset seizure, Computational study, Anticonvulsant, General Medicine
Abstract

In the past two decades, there has been sudden development in antiepileptic drugs (AEDs) for the adjunctive treatment of epilepsy. CNB is a leading-edge new generation tetrazole-derived carbamate for the treatment of focal-onset epileptic seizures where the mode of action is mediated by blocking voltage-gated sodium channels and interaction with the GABAergic system. The US FDA approved CNB with new hope for superior control over seizure, better safety, and tolerability profile compared to earlier AEDs.

Published
2023

44. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author

Shen, Hui, Fridley, Brooke L, Song, Honglin, Lawrenson, Kate, Cunningham, Julie M, Ramus, Susan J, Cicek, Mine S, Tyrer, Jonathan, Stram, Douglas, Larson, Melissa C, Köbel, Martin, Ziogas, Argyrios, Zheng, Wei, Yang, Hannah P, Wu, Anna H, Wozniak, Eva L, Ling Woo, Yin, Winterhoff, Boris, Wik, Elisabeth, Whittemore, Alice S, Wentzensen, Nicolas, Palmieri Weber, Rachel, Vitonis, Allison F, Vincent, Daniel, Vierkant, Robert A, Vergote, Ignace, Van Den Berg, David, Van Altena, Anne M, Tworoger, Shelley S, Thompson, Pamela J, Tessier, Daniel C, Terry, Kathryn L, Teo, Soo-Hwang, Templeman, Claire, Stram, Daniel O, Southey, Melissa C, Sieh, Weiva, Siddiqui, Nadeem, Shvetsov, Yurii B, Shu, Xiao-Ou, Shridhar, Viji, Wang-Gohrke, Shan, Severi, Gianluca, Schwaab, Ira, Salvesen, Helga B, Rzepecka, Iwona K, Runnebaum, Ingo B, Anne Rossing, Mary, Rodriguez-Rodriguez, Lorna, Risch, Harvey A, Renner, Stefan P, Poole, Elizabeth M, Pike, Malcolm C, Phelan, Catherine M, Pelttari, Liisa M, Pejovic, Tanja, Paul, James, Orlow, Irene, Zawiah Omar, Siti, Olson, Sara H, Odunsi, Kunle, Nickels, Stefan, Nevanlinna, Heli, Ness, Roberta B, Narod, Steven A, Nakanishi, Toru, Moysich, Kirsten B, Monteiro, Alvaro NA, Moes-Sosnowska, Joanna, Modugno, Francesmary, Menon, Usha, McLaughlin, John R, McGuire, Valerie, Matsuo, Keitaro, Mat Adenan, Noor Azmi, Massuger, Leon FAG, Lurie, Galina, Lundvall, Lene, Lubiński, Jan, Lissowska, Jolanta, Levine, Douglas A, Leminen, Arto, Lee, Alice W, Le, Nhu D, Lambrechts, Sandrina, Lambrechts, Diether, Kupryjanczyk, Jolanta, Krakstad, Camilla, Konecny, Gottfried E, Krüger Kjaer, Susanne, Kiemeney, Lambertus A, Kelemen, Linda E, Keeney, Gary L, Karlan, Beth Y, Karevan, Rod, Kalli, Kimberly R, Kajiyama, Hiroaki, Ji, Bu-Tian, Jensen, Allan, and Jakubowska, Anna

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, PRACTICAL Consortium, Australian Ovarian Cancer Study Group, Australian Cancer Study
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.

Published
2013

50. High-Pressure Delivery of Oncolytic Viruses via Needle-Free Injection Preserves Therapeutic Activity.

Author

Said, Aida, Hoang, Huy-Dung, Earl, Nathalie, Xiang, Xiao, Siddiqui, Nadeem, Côté, Marceline, and Alain, Tommy

Subjects
BIOLOGICAL models, INJECTIONS, STOMATITIS, ANIMAL experimentation, ANTINEOPLASTIC agents, MEDICAL technology, RNA, TREATMENT effectiveness, TUMORS, OXIDOREDUCTASES, ONCOLYTIC virotherapy, MICE, DNA viruses, EVALUATION
Abstract

Simple Summary: We explored the use of needle-free injection (NFI) technology to deliver oncolytic viruses (OVs) for treating solid tumours. The study assesses the infectivity of OVs following NFI and compares the effectiveness of intratumoural administration of Vesicular Stomatitis Virus (VSV) to that of traditional needle injection (NI) in subcutaneous tumours in mice. NFI improves viral tissue distribution and preserves therapeutic activity of this virotherapy. The study establishes NFI as an efficient delivery method for OVs and underscores the need for further optimization to enhance therapeutic efficacy. Intratumoural delivery of oncolytic viruses (OVs) to solid tumours is currently performed via multiple percutaneous methods of needle injections (NI). In this study, we investigated the potential use of a novel delivery approach, needle-free injection (NFI), to administer OVs to subcutaneous tumours. The stability and genetic integrity of several RNA and DNA viruses exposed to high-pressure jet injectors were first evaluated in vitro. We demonstrate that replication competence and infectivity of the viruses remained unchanged after NFI, as compared to traditional NI. Using the oncolytic Vesicular Stomatitis Virus expressing luciferase (VSVΔ51-Luc) in the syngeneic CT26 subcutaneous tumour model, we show that NFI administration not only successfully delivers infectious particles but also increases the dissemination of the virus within the tumour tissues when compared to NI. Furthermore, mice treated with VSVΔ51-Luc by NFI delivery showed similar reduction in tumour growth and survival compared to those with needle-administered virus. These results indicate that NFI represents a novel approach to administer and potentially increase the spread of OVs within accessible solid tumours, highlighting its usefulness in virotherapy. [ABSTRACT FROM AUTHOR]

Published
2023
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