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1. The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

Author: Cecilie Melau, Malene Lundgaard Riis, John E. Nielsen, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Mette Schou Hammerum, Rod T. Mitchell, Hanne Frederiksen, Anders Juul, and Anne Jørgensen
Subjects: Human, Adrenal, Ex vivo, Steroid hormones, ACTH, Osilodrostat, Medicine
Abstract: Abstract Background Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions. Methods This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8–12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey’s multiple comparisons test. Results Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions. Conclusions Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.
Published: 2021
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2. A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion

Author: Carla A. Gonçalves, Michael Larsen, Sascha Jung, Johannes Stratmann, Akiko Nakamura, Marit Leuschner, Lena Hersemann, Rashmiparvathi Keshara, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Ido Amit, Anne Jørgensen, Yung Hae Kim, Antonio del Sol, and Anne Grapin-Botton
Subjects: Science
Abstract: From single-cell transcriptome analyses to defining culture media for spheroids, the authors provide a census of information to understand the development of human pancreatic progenitors. This approach identifies signalling pathways (EGF and FGF) regulating progenitor proliferation.
Published: 2021
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3. Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis

Author: Anne Jørgensen, Joni Macdonald, John E. Nielsen, Karen R. Kilcoyne, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Hanne Frederiksen, Anna-Maria Andersson, Niels E. Skakkebæk, Anders Juul, Richard M. Sharpe, Ewa Rajpert-De Meyts, and Rod T. Mitchell
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. : Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer. Keywords: Nodal, Activin, human fetal testis, testicular germ cell cancer, testicular dysgenesis syndrome, ex vivo culture, xenografting, testicular development, gonocytes, pluripotency factors
Published: 2018
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4. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Author: Madalene Earp, Jonathan P Tyrer, Stacey J Winham, Hui-Yi Lin, Ganna Chornokur, Joe Dennis, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Høgdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Audrey Y Jung, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Boon Kiong Lim, Susanne K Kjaer, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Shashi Lele, Jenny Lester, Douglas A Levine, Zheng Li, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, James Paul, Tanja Pejovic, Liisa M Pelttari, Jenny B Permuth, Malcolm C Pike, Elizabeth M Poole, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Ingo B Runnebaum, Iwona K Rzepecka, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Liv Cecilie Vestrheim Thomsen, Robert A Vierkant, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Yin-Ling Woo, Anna H Wu, Xifeng Wu, Yong-Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alice W Lee, Celeste L Pearce, Andrew Berchuck, Joellen M Schildkraut, Susan J Ramus, Alvaro N A Monteiro, Steven A Narod, Thomas A Sellers, Simon A Gayther, Linda E Kelemen, Georgia Chenevix-Trench, Harvey A Risch, Paul D P Pharoah, Ellen L Goode, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: 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.
Published: 2018
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5. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Linda E. Kelemen, Madalene Earp, Brooke L. Fridley, Georgia Chenevix-Trench, on behalf of Australian Ovarian Cancer Study Group, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Diether Lambrechts, Sandrina Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang-Claude, Sabine Behrens, Kirsten B. Moysich, Rikki Cannioto, Shashikant Lele, Kunle Odunsi, Marc T. Goodman, Yurii B. Shvetsov, Pamela J. Thompson, Lynne R. Wilkens, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Peter Hillemanns, Ingo B. Runnebaum, Andreas du Bois, Philipp Harter, Florian Heitz, Ira Schwaab, Ralf Butzow, Liisa M. Pelttari, Heli Nevanlinna, Francesmary Modugno, Robert P. Edwards, Joseph L. Kelley, Roberta B. Ness, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine Walsh, Susanne K. Kjaer, Allan Jensen, Julie M. Cunningham, Robert A. Vierkant, Graham G. Giles, Fiona Bruinsma, Melissa C. Southey, Michelle A.T. Hildebrandt, Dong Liang, Karen Lu, Xifeng Wu, Thomas A. Sellers, Douglas A. Levine, Joellen M. Schildkraut, Edwin S. Iversen, Kathryn L. Terry, Daniel W. Cramer, Shelley S. Tworoger, Elizabeth M. Poole, Elisa V. Bandera, Sara H. Olson, Irene Orlow, Liv Cecilie Vestrheim Thomsen, Line Bjorge, Camilla Krakstad, Ingvild L. Tangen, Lambertus A. Kiemeney, Katja K.H. Aben, Leon F.A.G. Massuger, Anne M. van Altena, Tanja Pejovic, Yukie Bean, Melissa Kellar, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson, Jacek Gronwald, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Estrid Hogdall, Svend Aage Engelholm, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Paul D.P. Pharoah, Ed Dicks, Honglin Song, Jonathan P. Tyrer, Iain McNeish, Nadeem Siddiqui, Karen Carty, Rosalind Glasspool, James Paul, Ian G. Campbell, Diana Eccles, Alice S. Whittemore, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Steven A. Narod, Catherine M. Phelan, John R. McLaughlin, Harvey A. Risch, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A. Gayther, Aleksandra Gentry-Maharaj, Susan J. Ramus, Anna H. Wu, Celeste Leigh Pearce, Alice W. Lee, Malcolm C. Pike, Jolanta Kupryjanczyk, Agnieszka Podgorska, Joanna Plisiecka-Halasa, Wlodzimierz Sawicki, Ellen L. Goode, Andrew Berchuck, and Ovarian Cancer Association Consortium
Subjects: consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Biology (General), QH301-705.5, Chemistry, QD1-999
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
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6. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Author: Ganna Chornokur, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ernest K Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S L Jim, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Linda E Kelemen, Mellissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Robert A Vierkant, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N Hasmad, Andrew Berchuck, Georgia Chenevix-Trench, AOCS management group, Edwin S Iversen, Joellen M Schildkraut, Susan J Ramus, Ellen L Goode, Alvaro N A Monteiro, Simon A Gayther, Steven A Narod, Paul D P Pharoah, Thomas A Sellers, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: BACKGROUND:Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS:In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q
Published: 2015
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7. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium.

Author: Ernest K Amankwah, Qinggang Wang, Joellen M Schildkraut, Ya-Yu Tsai, Susan J Ramus, Brooke L Fridley, Jonathan Beesley, Sharon E Johnatty, Penelope M Webb, Georgia Chenevix-Trench, Australian Ovarian Cancer Study Group, Laura C Dale, Diether Lambrechts, Frederic Amant, Evelyn Despierre, Ignace Vergote, Simon A Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Jenny Chang-Claude, Shan Wang-Gohrke, Hoda Anton-Culver, Argyrios Ziogas, Thilo Dörk, Matthias Dürst, Natalia Antonenkova, Natalia Bogdanova, Robert Brown, James M Flanagan, Stanley B Kaye, James Paul, Ralf Bützow, Heli Nevanlinna, Ian Campbell, Diana M Eccles, Beth Y Karlan, Jenny Gross, Christine Walsh, Paul D P Pharoah, Honglin Song, Susanne Krüger Kjær, Estrid Høgdall, Claus Høgdall, Lene Lundvall, Lotte Nedergaard, Lambertus A L M Kiemeney, Leon F A G Massuger, Anne M van Altena, Sita H H M Vermeulen, Nhu D Le, Angela Brooks-Wilson, Linda S Cook, Catherine M Phelan, Julie M Cunningham, Celine M Vachon, Robert A Vierkant, Edwin S Iversen, Andrew Berchuck, Ellen L Goode, Thomas A Sellers, and Linda E Kelemen
Subjects: Medicine, Science
Abstract: Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
Published: 2011
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8. Supplementary Tables 1 - 4 from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau
Abstract: PDF file - 157K, Supplemental Table 1. Regulatory T cell genes included in this study (N=25). Supplemental Table 2. Regulatory T cell SNPs included in this study. Supplemental Table 3. Participating invasive epithelial ovarian cancer studies. Supplemental Table 4. Association between clinical variables and overall survival.
Published: 2023

9. Data from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
Published: 2023

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

Author: Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar
Abstract: Background: 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.Methods: 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).Results: 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.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2023

11. Supplementary Figures 1-5, Tables 1-8 from Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author: Georgia Chenevix-Trench, Penelope M. Webb, Anna deFazio, Ellen L. Goode, Paul D.P. Pharoah, Stuart MacGregor, Andrew Berchuck, Yoke-Eng Chiew, Catherine Kennedy, Thomas Sellers, Rosalind Glasspool, Nadeem Siddiqui, Karen Carty, James Paul, Ian McNeish, Lene Lundvall, Claus Høgdall, Yukie Bean, Tanja Pejovic, Irene Orlow, Elisa V. Bandera, Daniel W. Cramer, Kathryn L. Terry, Edwin S. Iversen, Joellen M. Schildkraut, Robert A. Vierkant, Julie M. Cunningham, Brooke L. Fridley, Susanne Kruger Kjaer, Allan Jensen, Estrid Høgdall, Zachary C. Fogarty, Melissa C. Larson, Madalene Earp, Stacey J. Winham, Sandra Orsulic, Jenny Lester, Christine Walsh, Beth Y. Karlan, Peter Hillemanns, Jacobus Pisterer, Philipp Harter, Ira Schwaab, Andreas du Bois, Florian Heitz, Pamela J. Thompson, Michael E. Carney, Lynne R. Wilkens, Marc T. Goodman, Beata Spiewankiewicz, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Celeste L. Pearce, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Simon A. Gayther, Argyrios Ziogas, Hoda Anton-Culver, Rebecca Sutphen, Joseph H. Rothstein, Valerie McGuire, Alice S. Whittemore, Weiva Sieh, Diana Eccles, Ian Campbell, Valerie Rhenius, Honglin Song, Nicolas Wentzensen, Jolanta Lissowska, Louise Brinton, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Douglas A. Levine, Kirsten B. Moysich, Roberta B. Ness, Francesmary Modugno, Jenny Chang-Claude, Jennifer A. Doherty, Mary Anne Rossing, Sandrina Lambrechts, Ignace Vergote, Els Van Nieuwenhuysen, Diether Lambrechts, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Peter A. Fasching, Bo Gao, Yi Lu, Jonathan Beesley, Siddhartha Kar, Jonathan P. Tyrer, and Sharon E. Johnatty
Abstract: Supplementary Figures 1-5, Tables 1-8. Supplementary Figure 1: Overview of the analytic approach. Supplementary Figure 2: QQ plots of SNPs with MAF â‰¥0.02 and imputation r2 â‰¥0.9 associated with Overall Survival in A. Supplementary Figure 3: â€˜All OCACâ€™ histology-adjusted analysis. Supplementary Figure 4: Forest plots of promising SNPs. Supplementary Figure 5: KM-Plotter graphs of significant associations with outcome. Supplementary Table 1: All studies (OCAC & TCGA) eligible for analyses according to first-line chemotherapy. Supplementary Table 2: Description of individual OCAC studies included in the secondary 'all OCAC' analysis. Supplementary Table 3a: Overall Survival estimates for selected SNPs (MAF â‰¥0.02) comparing iCOGS imputed (r2 â‰¥0.3) and iPLEX genotyped samples. Supplementary Table 3b: Progression-free Survival estimates for selected SNPs (MAF â‰¥0.02) comparing iCOGS imputed (r2 â‰¥0.3) and iPLEX genotyped samples. Supplementary Table 4: SNPs with imputation r2 â‰¥0.9, EAF â‰¥0.02 and p â‰¤ 1E-05 for at least one of four outcomes analyzed in cases selected according to first-line chemotherapy. Supplementary Table 5: Meta-analysis of largest possible sample (TCGA, non-overlapping iCOGS and iplex genotyped) for selected promising SNPs analyzed in cases selected according to first-line chemotherapy. Supplementary Table 6: Significant association between protein-coding genes within 1Mb of promising SNPs and ovarian cancer outcomes. Supplementary Table 7: SNPs with imputation r-sqâ‰¥0.9 and p â‰¤ 1E-05 for Overall Survival in histology-adj 'all OCAC' analysis. Supplementary Table 8: iCOGS estimates for SNPs previously identified to be associated with response to chemotherapy as reported in the aNHGRI GWAS catalog.
Published: 2023

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

Author: Georgia Chenevix-Trench, Penelope M. Webb, Anna deFazio, Ellen L. Goode, Paul D.P. Pharoah, Stuart MacGregor, Andrew Berchuck, Yoke-Eng Chiew, Catherine Kennedy, Thomas Sellers, Rosalind Glasspool, Nadeem Siddiqui, Karen Carty, James Paul, Ian McNeish, Lene Lundvall, Claus Høgdall, Yukie Bean, Tanja Pejovic, Irene Orlow, Elisa V. Bandera, Daniel W. Cramer, Kathryn L. Terry, Edwin S. Iversen, Joellen M. Schildkraut, Robert A. Vierkant, Julie M. Cunningham, Brooke L. Fridley, Susanne Kruger Kjaer, Allan Jensen, Estrid Høgdall, Zachary C. Fogarty, Melissa C. Larson, Madalene Earp, Stacey J. Winham, Sandra Orsulic, Jenny Lester, Christine Walsh, Beth Y. Karlan, Peter Hillemanns, Jacobus Pisterer, Philipp Harter, Ira Schwaab, Andreas du Bois, Florian Heitz, Pamela J. Thompson, Michael E. Carney, Lynne R. Wilkens, Marc T. Goodman, Beata Spiewankiewicz, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Celeste L. Pearce, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Simon A. Gayther, Argyrios Ziogas, Hoda Anton-Culver, Rebecca Sutphen, Joseph H. Rothstein, Valerie McGuire, Alice S. Whittemore, Weiva Sieh, Diana Eccles, Ian Campbell, Valerie Rhenius, Honglin Song, Nicolas Wentzensen, Jolanta Lissowska, Louise Brinton, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Douglas A. Levine, Kirsten B. Moysich, Roberta B. Ness, Francesmary Modugno, Jenny Chang-Claude, Jennifer A. Doherty, Mary Anne Rossing, Sandrina Lambrechts, Ignace Vergote, Els Van Nieuwenhuysen, Diether Lambrechts, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Peter A. Fasching, Bo Gao, Yi Lu, Jonathan Beesley, Siddhartha Kar, Jonathan P. Tyrer, and Sharon E. Johnatty
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental Design: We 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.Results: Five 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).Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.
Published: 2023

13. Data from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author: Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block
Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.
Published: 2023

14. Supplementary Tables 1 through 3 from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author: Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block
Abstract: PDF - 149K, Supplemental Table 1. Participating invasive epithelial ovarian cancer studies. Supplementary Table 2. NF-κB genes studied. Supplemental Table 3. Association between clinical variables and overall survival.
Published: 2023

15. Data from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author: Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode
Abstract: Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality.Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths).Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3–2.2, P = 2.0 × 10−5) and with overall variation in HGF (gene-level test, P = 3.7 × 10−4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r2 = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4–4.1, P = 2.2 × 10−3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3–1.9, P = 7.0 × 10−5] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9–1.1, P = 0.87).Conclusions: We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression.Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies. Cancer Epidemiol Biomarkers Prev; 20(8); 1638–48. ©2011 AACR.
Published: 2023

16. Supplementary Tables 1-7 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author: Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode
Abstract: Supplementary Tables 1-7 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality
Published: 2023

17. Supplementary Figures 1-4 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author: Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode
Abstract: Supplementary Figures 1-4 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality
Published: 2023

18. Supplementary Tables S1-6, Figures S1-2 from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar
Abstract: Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network
Published: 2023

19. Data from Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Author: Ellen L. Goode, Brooke L. Fridley, Julie M. Cunningham, Keith L. Knutson, Kirsten Moysich, Paul D.P. Pharoah, Linda E. Kelemen, Piotr Sobiczewski, Michelle A.T. Hildebrandt, Montserrat Garcia-Closas, Ignace Vergote, Joseph H. Rothstein, Grace Friel, Francesmary Modugno, Arto Leminen, Lynne R. Wilkens, Arif B. Ekici, Janusz Menkiszak, Urmila Chandran, Ira Schwaab, Aleksandra Gentry-Maharaj, Mari K. Halle, David van den Berg, Anne M. Van Altena, Liisa M. Pelttari, Matthias W. Beckmann, Hannah Yang, Sandrina Lambrechts, Lukasz M. Szafron, Shan Wang-Gohrke, Lene Lundvall, Andreas du Bois, Jenny Lester, Valerie McGuire, Robert Edwards, Lara Sucheston, Jie Lin, Cezary Cybulski, Elisabeth Wik, Susan J. Ramus, Malcolm C. Pike, Katja K. Aben, Angela Brooks-Wilson, Allison F. Vitonis, Jonathan Tyrer, Philipp Harter, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Anja Rudolph, Alexander Hein, Louise Brinton, Evelyn Despierre, Christine Walsh, Argyrios Ziogas, Galina Lurie, Yukie T. Bean, Heli Nevanlinna, Jan Lubiński, Allan Jensen, Andrew Berchuck, Kunle Odunsi, Dong Liang, Camilla Krakstad, Jennifer A. Doherty, Honglin Song, Leon F.A.G. Massuger, Robert Brown, Catherine M. Phelan, James M. Flanagan, Daniel Cramer, Susanne Kruger Kjaer, Douglas A. Levine, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Peter A. Fasching, Diether Lambrechts, Claus K. Hogdall, Jacek Gronwald, Hoda Anton-Culver, Beth Y. Karlan, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Simon A. Gayther, Anna H. Wu, James Paul, Diana Eccles, Ingo B. Runnebaum, Natalia Bogdanova, Clareann H. Bunker, Nhu D. Le, Ian Campbell, Tanja Pejovic, Thilo Dörk, Ralf Butzow, Karen Lu, Jolanta Kupryjanczyk, Steven A. Narod, Roberta B. Ness, Mary Anne Rossing, Linda S. Cook, Pamela J. Thompson, Marc T. Goodman, Kathryn Terry, Irene Orlow, Elisa V. Bandera, Jenny Chang-Claude, Weiva Sieh, Alice S. Whittemore, Georgia Chenevix-Trench, Nicolas Wentzensen, Britton Trabert, Gianluca Severi, Graham G. Giles, Laura Baglietto, Lambertus A. Kiemeney, Helga B. Salvesen, Harvey A. Risch, Elizabeth Poole, Shelley S. Tworoger, Thomas A. Sellers, David N. Rider, Zachary Fogarty, Kimberly R. Kalli, Robert A. Vierkant, William R. Bamlet, Matthew S. Block, and Bridget Charbonneau
Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.
Published: 2023

20. Supplementary Tables 1 - 5 from Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Author: Ellen L. Goode, Brooke L. Fridley, Julie M. Cunningham, Keith L. Knutson, Kirsten Moysich, Paul D.P. Pharoah, Linda E. Kelemen, Piotr Sobiczewski, Michelle A.T. Hildebrandt, Montserrat Garcia-Closas, Ignace Vergote, Joseph H. Rothstein, Grace Friel, Francesmary Modugno, Arto Leminen, Lynne R. Wilkens, Arif B. Ekici, Janusz Menkiszak, Urmila Chandran, Ira Schwaab, Aleksandra Gentry-Maharaj, Mari K. Halle, David van den Berg, Anne M. Van Altena, Liisa M. Pelttari, Matthias W. Beckmann, Hannah Yang, Sandrina Lambrechts, Lukasz M. Szafron, Shan Wang-Gohrke, Lene Lundvall, Andreas du Bois, Jenny Lester, Valerie McGuire, Robert Edwards, Lara Sucheston, Jie Lin, Cezary Cybulski, Elisabeth Wik, Susan J. Ramus, Malcolm C. Pike, Katja K. Aben, Angela Brooks-Wilson, Allison F. Vitonis, Jonathan Tyrer, Philipp Harter, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Anja Rudolph, Alexander Hein, Louise Brinton, Evelyn Despierre, Christine Walsh, Argyrios Ziogas, Galina Lurie, Yukie T. Bean, Heli Nevanlinna, Jan Lubiński, Allan Jensen, Andrew Berchuck, Kunle Odunsi, Dong Liang, Camilla Krakstad, Jennifer A. Doherty, Honglin Song, Leon F.A.G. Massuger, Robert Brown, Catherine M. Phelan, James M. Flanagan, Daniel Cramer, Susanne Kruger Kjaer, Douglas A. Levine, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Peter A. Fasching, Diether Lambrechts, Claus K. Hogdall, Jacek Gronwald, Hoda Anton-Culver, Beth Y. Karlan, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Simon A. Gayther, Anna H. Wu, James Paul, Diana Eccles, Ingo B. Runnebaum, Natalia Bogdanova, Clareann H. Bunker, Nhu D. Le, Ian Campbell, Tanja Pejovic, Thilo Dörk, Ralf Butzow, Karen Lu, Jolanta Kupryjanczyk, Steven A. Narod, Roberta B. Ness, Mary Anne Rossing, Linda S. Cook, Pamela J. Thompson, Marc T. Goodman, Kathryn Terry, Irene Orlow, Elisa V. Bandera, Jenny Chang-Claude, Weiva Sieh, Alice S. Whittemore, Georgia Chenevix-Trench, Nicolas Wentzensen, Britton Trabert, Gianluca Severi, Graham G. Giles, Laura Baglietto, Lambertus A. Kiemeney, Helga B. Salvesen, Harvey A. Risch, Elizabeth Poole, Shelley S. Tworoger, Thomas A. Sellers, David N. Rider, Zachary Fogarty, Kimberly R. Kalli, Robert A. Vierkant, William R. Bamlet, Matthew S. Block, and Bridget Charbonneau
Abstract: PDF file - 145K, Supplementary Table 1. Studies in the Ovarian Cancer Association Consortium (OCAC) are listed, as well as the abbreviation, location, type, and number of cases and controls for each study. Supplementary Table 2. The number of cases included in the analysis from each OCAC study site is listed by histologic subtype. Supplementary Table 3. Gene symbols and IDs are listed for NF-κB pathway genes that were tagged in this study, as well as chromosome position, number of SNPs tagged, and bin coverage of each gene using Hapmap or 1000 genomes as a reference. Supplementary Table 4. Reasons and numbers of samples excluded from the analysis following the sample quality control are described. Supplementary Table 5. We evaluated rs17561 and rs6785617 for interactions with known epidemiologic risk factors for risk of clear cell and LMP tumors, respectively, and report interaction p-values in the table below.
Published: 2023

21. The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

Author: Lea Langhoff Thuesen, Cecilie Melau, John E Nielsen, Lene Lundvall, Mette Schou Hammerum, Malene Lundgaard Riis, Anders Juul, Kristine Juul Hare, Rod T. Mitchell, Anne Jørgensen, Signe Perlman, and Hanne Frederiksen
Subjects: medicine.medical_specialty, Adrenal disorder, medicine.medical_treatment, Adrenocorticotropic hormone, Fetus, Adrenocorticotropic Hormone, In vivo, Internal medicine, Adrenal Glands, medicine, Humans, Adrenal, Abiraterone, Osilodrostat, Steroid hormones, business.industry, Steroid 17-alpha-Hydroxylase, Adrenal crisis, General Medicine, Ex vivo, ACTH, Steroid hormone, Endocrinology, CYP17A1, Medicine, Female, Steroids, Steroid 21-Hydroxylase, Efavirenz, medicine.symptom, business, Research Article, Human
Abstract: Background Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions. Methods This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8–12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey’s multiple comparisons test. Results Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions. Conclusions Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.
Published: 2021

22. A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion

Author: Yung Hae Kim, Anne Grapin-Botton, Rashmiparvathi Keshara, Signe Perlman, Sascha Jung, Antonio del Sol, Michael Larsen, Carla A C Gonçalves, Akiko Nakamura, Kristine J. Hare, Lene Lundvall, Lena Hersemann, Johannes Stratmann, Ido Amit, Lea Langhoff Thuesen, Anne Jørgensen, and Marit Leuschner
Subjects: 0301 basic medicine, Organogenesis, Cellular differentiation, Cell Culture Techniques, Datasets as Topic, General Physics and Astronomy, Cell Communication, Fibroblast growth factor, Tissue Culture Techniques, Transcriptome, Mice, 0302 clinical medicine, RNA-Seq, RNA-SEQ, Induced pluripotent stem cell, ORGANOGENESIS, Multidisciplinary, Gene Expression Regulation, Developmental, Cell Differentiation, Cell biology, DIFFERENTIATION, medicine.anatomical_structure, Aborted Fetus, Single-Cell Analysis, Pancreas, Signal Transduction, Pluripotent Stem Cells, EXPRESSION, Cell signaling, TISSUES, Science, Stem-cell differentiation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, BETA-CELLS, Spheroids, Cellular, REVEALS, medicine, Animals, Humans, Progenitor cell, Progenitor, Epidermal Growth Factor, IN-VITRO, General Chemistry, Embryo, Mammalian, DYSFUNCTION, Fibroblast Growth Factors, 030104 developmental biology, 030217 neurology & neurosurgery, GENERATION
Abstract: Human organogenesis remains relatively unexplored for ethical and practical reasons. Here, we report the establishment of a single-cell transcriptome atlas of the human fetal pancreas between 7 and 10 post-conceptional weeks of development. To interrogate cell–cell interactions, we describe InterCom, an R-Package we developed for identifying receptor–ligand pairs and their downstream effects. We further report the establishment of a human pancreas culture system starting from fetal tissue or human pluripotent stem cells, enabling the long-term maintenance of pancreas progenitors in a minimal, defined medium in three-dimensions. Benchmarking the cells produced in 2-dimensions and those expanded in 3-dimensions to fetal tissue identifies that progenitors expanded in 3-dimensions are transcriptionally closer to the fetal pancreas. We further demonstrate the potential of this system as a screening platform and identify the importance of the EGF and FGF pathways controlling human pancreas progenitor expansion., From single-cell transcriptome analyses to defining culture media for spheroids, the authors provide a census of information to understand the development of human pancreatic progenitors. This approach identifies signalling pathways (EGF and FGF) regulating progenitor proliferation.
Published: 2021

23. Establishment of a Novel Human Fetal Adrenal Culture Model that Supports de Novo and Manipulated Steroidogenesis

Author: Rod T. Mitchell, Kristine J. Hare, Mette Schou Hammerum, Cecilie Melau, Lene Lundvall, Lea Langhoff Thuesen, Anders Juul, Anne Jørgensen, Hanne Frederiksen, John E. Nielsen, and Signe Perlman
Subjects: 0301 basic medicine, medicine.medical_specialty, steroidogenesis, Adrenal disorder, Cell Survival, Endocrinology, Diabetes and Metabolism, Primary Cell Culture, Clinical Biochemistry, ketoconazole, Drug Evaluation, Preclinical, 030209 endocrinology & metabolism, Adrenocorticotropic hormone, endocrine activity, Models, Biological, Biochemistry, 03 medical and health sciences, Fetus, 0302 clinical medicine, Endocrinology, ex vivo culture, Adrenocorticotropic Hormone, Pregnancy, Internal medicine, Adrenal Glands, medicine, Humans, Endocrine system, Congenital adrenal hyperplasia, androgen biosynthesis, Glucocorticoids, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), medicine.disease, Culture Media, Androgen secretion, ACTH, Ketoconazole, 030104 developmental biology, Androgens, Female, Steroids, business, Metabolic Networks and Pathways, Ex vivo, Hormone
Abstract: Context Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail. Objective Due to significant differences in adrenal steroidogenesis between human and model species (except higher primates), we aimed to establish a human fetal adrenal model that enables examination of both de novo and manipulated adrenal steroidogenesis. Design and Setting Human adrenal tissue from 54 1st trimester fetuses were cultured ex vivo as intact tissue fragments for 7 or 14 days. Main Outcome Measures Model validation included examination of postculture tissue morphology, viability, apoptosis, and quantification of steroid hormones secreted to the culture media measured by liquid chromatography-tandem mass spectrometry. Results The culture approach maintained cell viability, preserved cell populations of all fetal adrenal zones, and recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens. Adrenocorticotropic hormone and ketoconazole treatment of ex vivo cultured human fetal adrenal tissue resulted in the stimulation of steroidogenesis and inhibition of androgen secretion, respectively, demonstrating a treatment-specific response. Conclusions Together, these data indicate that ex vivo culture of human fetal adrenal tissue constitutes a novel approach to investigate local effects of pharmaceutical exposures or emerging therapeutic options targeting imbalanced steroidogenesis in adrenal disorders, including CAH.
Published: 2021

24. 241 When MDT interdisciplinarity enhances stringency and professional quality; an analysis of multi-disciplinary team conferences

Author: Rikke Hagemann-Madsen, Lone Nørgård Petersen, Sigrid Kasper Fog, Merete Watt Boolsen, Jon Asmussen, Jens Hillingsø, Torben Riis Rasmussen, Pernille Dehn, Lene Lundvall, and Michael Borre
Subjects: Medical education, business.industry, media_common.quotation_subject, Guideline, Multidisciplinary team, language.human_language, Task (project management), Danish, Multidisciplinary approach, Health care, language, Quality (business), business, Psychology, Theoretic model, media_common
Abstract: Introduction/Background In 2016 the Danish Multidisciplinary Cancer Group’s (DMCG) national Multidisciplinary Team (MDT) working committee established recommended quality standards in Danish healthcare. This current study investigates the status of implementation of the guideline published in 2016 amongst the clinicians who now manages and carry out the developed guideline at the MDT conference. The aims are to identify challenges and successful initiatives based on individual experiences and to point out areas of development within the MDT conference. Methodology The study is conducted as a social scientific questionnaire using the complexity theoretic model by Ralph Stacey, designed using MSC (Most Significant Change technique) which focusses on development and dynamics in organizations that are constantly and rapidly changing. 618 participants were identified and invited by either their own MDT leader or by a contact person appointed by the chairman of the cancer group. Results Answers were calculated using selective coding resulting in themes leading to the following outcome: The MDT conference is a well-established part of clinical practice, and are perceived as significant, qualified and qualifying; Measures that can further qualify the conference decision include more time for the task; A spinoff effect is identified on the conference participants’ social and professional relationship, which are developed, valued and supported in relation to the meetings Conclusion Multiple opportunities for improvement and future development potentials are presented in this article Disclosures The authors have nothing to disclose. ICMJE forms signed. Funding and Trial registration Funding by the Danish Multidisciplinary Cancer Group (DMCG) and the Danish Cancer Collaboration Center (DCCC)
Published: 2020

25. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Author: Scott H. Kaufmann, Daniel Guimarães Tiezzi, Valerie Rhenius, Gary L. Keeney, Alexander Hein, Dominique-Laurent Couturier, Florin Andrei Taran, Robert Edwards, Aline Talhouk, Stacey J. Winham, Christiani Bisinoto de Sousa, Nadja Pejovic, Andreas D. Hartkopf, Ramona Erber, Brenda Y. Hernandez, Jenny Lester, Teri A. Longacre, Anna L. Paterson, Peter Sinn, Robin Crawford, Lene Lundvall, Hugh Luk, Roberta B. Ness, Adekunle Odunsi, Suha Deen, Javier Benitez, Alice S. Whittemore, Anna Fischer, Anthony N. Karnezis, Christine Chow, Ana Osorio, Ellen L. Goode, Stefan Kommoss, Angela Brooks-Wilson, Linda E. Kelemen, Tanja Pejovic, Simon A. Gayther, Peter A. Fasching, Beth Y. Karlan, Jurandyr Moreira de Andrade, Samuel Leung, David D.L. Bowtell, James D. Brenton, Aleksandra Vrvilo, Marc T. Goodman, Paul D.P. Pharoah, Sara Y. Brucker, Honglin Song, Jennifer M Koziak, Robert A. Vierkant, Naveena Singh, Valerie McGuire, Chloe Karpinskyj, Mercedes Jimenez-Linan, Aleksandra Gentry-Maharaj, Anna deFazio, Jenny Chang-Claude, Linda S. Cook, Francesmary Modugno, Filipe C. Martins, Estrid Høgdall, Prafull Ghatage, Marie Lyne Alcaraz, Susan J. Ramus, Annette Staebler, Jennifer Alsop, David G. Huntsman, Joseph H. Rothstein, Tayyebeh M. Nazeran, Cristina Rodríguez-Antona, Luis Robles-Díaz, Bryan M. McCauley, María Jesús Gómez García, Michael E. Carney, Michael S. Anglesio, Yurii B. Shvetsov, Claus Høgdall, Sian Fereday, Martin Köbel, Maria P. Intermaggio, Sandra Orsulic, Luis Paz-Ares, Mary Anne Brett, Weiva Sieh, Matthias W. Beckmann, Helen Steed, Arndt Hartmann, Michael Schneider, Lynne R. Wilkens, Esther Herpel, Jacek Gronwald, Francisco José Candido dos Reis, Nhu D. Le, Gregg Nelson, Kirsten B. Moysich, Nadia Traficante, Usha Menon, Candido Dos Reis, Francisco J [0000-0001-5758-5917], Brenton, James D [0000-0002-5738-6683], Apollo - University of Cambridge Repository, Candido dos Reis, Francisco J. [0000-0001-5758-5917], and Brenton, James D. [0000-0002-5738-6683]
Subjects: Oncology, Cancer Research, 692/4028/67/1517/1709, Carcinoma, Ovarian Epithelial, Clear Cell, Androgen, ESTUDOS PROSPECTIVOS, Cohort Studies, Gene Knockout Techniques, 0302 clinical medicine, Ovarian carcinoma, Ovarian Epithelial, Receptors, Prospective Studies, Progesterone, Cancer, Ovarian Neoplasms, 0303 health sciences, Tumor, Molecular medicine, biology, Hazard ratio, article, Age Factors, Middle Aged, Ovarian Cancer, Serous fluid, Receptors, Estrogen, Receptors, Androgen, 030220 oncology & carcinogenesis, Public Health and Health Services, Biomarker (medicine), Female, Receptors, Progesterone, medicine.medical_specialty, Oncology and Carcinogenesis, Down-Regulation, Adenocarcinoma, 03 medical and health sciences, Rare Diseases, Ovarian cancer, Internal medicine, Progesterone receptor, medicine, Biomarkers, Tumor, PTEN, Humans, Oncology & Carcinogenesis, 030304 developmental biology, Neoplasm Staging, business.industry, Tumor Suppressor Proteins, Carcinoma, PTEN Phosphohydrolase, medicine.disease, Estrogen, 692/4017, Androgen receptor, Tissue Array Analysis, biology.protein, business, Biomarkers, Adenocarcinoma, Clear Cell
Abstract: Background PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Published: 2020
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26. Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes

Author: Signe Perlman, K. Harpelunde Poulsen, Rod T. Mitchell, John E Nielsen, Lene Lundvall, E. Rajpert-De Meyts, K Juul Hare, Hanne Frederiksen, A. Jørgensen, Cecilie Melau, L Langhoff Thuesen, and Anders Juul
Subjects: Fibroblast Growth Factor 9, Male, endocrine system, Somatic cell, Cell Survival, human fetal testis / human fetal ovary / ex vivo culture / FGF9 signalling / gonocytes / oogonia / gonadal sex differentiation / initiation of meiosis / somatic niche formation, Sertoli cell proliferation, Ovary, Biology, Andrology, 03 medical and health sciences, 0302 clinical medicine, Gonocyte, FGF9, Pregnancy, Wnt4 Protein, WNT4, Testis, medicine, Humans, Cell Lineage, Pyrroles, Receptor, Fibroblast Growth Factor, Type 1, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Reproductive Biology, 030219 obstetrics & reproductive medicine, Sertoli Cells, Rehabilitation, Obstetrics and Gynecology, Gene Expression Regulation, Developmental, Leydig Cells, Cell Differentiation, Sertoli cell, Pregnancy Trimester, First, medicine.anatomical_structure, Germ Cells, Reproductive Medicine, Original Article, Female, Germ cell, Signal Transduction
Abstract: STUDY QUESTION Does experimental manipulation of fibroblast growth factor 9 (FGF9)-signalling in human fetal gonads alter sex-specific gonadal differentiation? SUMMARY ANSWER Inhibition of FGFR signalling following SU5402 treatment impaired germ cell survival in both sexes and severely altered the developing somatic niche in testes, while stimulation of FGF9 signalling promoted Sertoli cell proliferation in testes and inhibited meiotic entry of germ cells in ovaries. WHAT IS KNOWN ALREADY Sex-specific differentiation of bipotential gonads involves a complex signalling cascade that includes a combination of factors promoting either testicular or ovarian differentiation and inhibition of the opposing pathway. In mice, FGF9/FGFR2 signalling has been shown to promote testicular differentiation and antagonize the female developmental pathway through inhibition of WNT4. STUDY DESIGN, SIZE, DURATION FGF signalling was manipulated in human fetal gonads in an established ex vivo culture model by treatments with recombinant FGF9 (25 ng/ml) and the tyrosine kinase inhibitor SU5402 (10 μM) that was used to inhibit FGFR signalling. Human fetal testis and ovary tissues were cultured for 14 days and effects on gonadal development and expression of cell lineage markers were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS Gonadal tissues from 44 male and 33 female embryos/fetuses from first trimester were used for ex vivo culture experiments. Tissues were analyzed by evaluation of histology and immunohistochemical analysis of markers for germ cells, somatic cells, proliferation and apoptosis. Culture media were collected throughout the experimental period and production of steroid hormone metabolites was analyzed in media from fetal testis cultures by liquid chromatography–tandem mass spectrometry (LC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE Treatment with SU5402 resulted in near complete loss of gonocytes (224 vs. 14 OCT4+ cells per mm2, P LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Ex vivo culture may not replicate all aspects of fetal gonadal development and function in vivo. Although the effects of FGF9 were studied in ex vivo culture experiments, there is no direct evidence that FGF9 acts in vivo during human fetal gonadogenesis. The FGFR inhibitor (SU5402) used in this study is not specific to FGFR2 but inhibits all FGF receptors and off-target effects on unrelated tyrosine kinases should be considered. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study suggest that dysregulation of FGFR-mediated signalling may affect both testicular and ovarian development, in particular impacting the fetal germ cell populations in both sexes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.JØ. Additional funding was obtained from the Erichsen Family Fund (A.JØ.), the Aase and Ejnar Danielsens Fund (A.JØ.), the Danish Government’s support for the EDMaRC programme (A.JU.) and a Wellcome Trust Intermediate Clinical Fellowship (R.T.M., Grant no. 098522). The Medical Research Council (MRC) Centre for Reproductive Health (R.T.M.) is supported by an MRC Centre Grant (MR/N022556/1). The authors have no conflict of interest to disclose.
Published: 2019

27. Tracing the origin of adult intestinal stem cells

Author: Kristine J. Hare, Svetlana Ulyanchenko, Agnete Larsen, Lea Langhoff Thuesen, Anne Jørgensen, Jordi Guiu, Rasmus H. Olesen, Shiro Yui, Signe Perlman, Edouard Hannezo, Tune H. Pers, Martti Maimets, Samuel Demharter, Benjamin D. Simons, Kim B. Jensen, Konstantin Khodosevich, Lene Lundvall, Linn Salto Mamsen, Claus Yding Andersen, Simons, Benjamin [0000-0002-3875-7071], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Cellular differentiation, Fetus/cytology, Biology, digestive system, Article, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, Fetus, 0302 clinical medicine, Intestinal mucosa, Stem Cells/cytology, Animals, Regeneration, Cell Lineage, Intestinal Mucosa, Stem Cell Niche, Intestinal Mucosa/cytology, Multidisciplinary, Stem Cells, LGR5, Cell Differentiation, Receptors, G-Protein-Coupled/metabolism, Cellular Reprogramming, Intestinal epithelium, Cell biology, Transplantation, Intestines, 030104 developmental biology, Female, Stem cell, Reprogramming, 030217 neurology & neurosurgery, Intestines/cytology, Adult stem cell
Abstract: Adult intestinal stem cells are located at the bottom of crypts of Lieberkuhn, where they express markers such as LGR51,2 and fuel the constant replenishment of the intestinal epithelium1. Although fetal LGR5-expressing cells can give rise to adult intestinal stem cells3,4, it remains unclear whether this population in the patterned epithelium represents unique intestinal stem-cell precursors. Here we show, using unbiased quantitative lineage-tracing approaches, biophysical modelling and intestinal transplantation, that all cells of the mouse intestinal epithelium—irrespective of their location and pattern of LGR5 expression in the fetal gut tube—contribute actively to the adult intestinal stem cell pool. Using 3D imaging, we find that during fetal development the villus undergoes gross remodelling and fission. This brings epithelial cells from the non-proliferative villus into the proliferative intervillus region, which enables them to contribute to the adult stem-cell niche. Our results demonstrate that large-scale remodelling of the intestinal wall and cell-fate specification are closely linked. Moreover, these findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissues following damage5–9, revealing that stem-cell identity is an induced rather than a hardwired property. Lineage tracing, biophysical modelling and intestinal transplantation approaches are used to demonstrate that, in the mouse fetal intestinal epithelium, cells are highly plastic with respect to cellular identity and, independent of LGR5 expression and cell position, can contribute to the adult stem cell compartment.
Published: 2019

28. SUN-039 Characterization of Human Adrenal Steroidogenesis during Fetal Development

Author: Cecilie Melau, Signe Perlman, Lene Lundvall, Kristine J. Hare, John E Nielsen, Rod T. Mitchell, Anders Juul, Lea Langhoff Thuesen, Karen Kilcoyne, Anna-Maria Andersson, Anne Jørgensen, and Hanne Frederiksen
Subjects: medicine.medical_specialty, Fetus, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Cholesterol side-chain cleavage enzyme, Context (language use), Biology, Genetics and Development (including Gene Regulation), Steroid hormone, How Genetics and Development Impact the Endocrine System, Endocrinology, CYP17A1, Internal medicine, medicine, Endocrine system, Steroid 11-beta-hydroxylase, Testosterone
Abstract: Context: The endocrine function of human fetal adrenals (HFA) is activated already during first trimester, but changes in adrenal steroidogenesis during fetal life are not well characterized. Objective: This study aimed to investigate HFA steroidogenesis by analyzing adrenal glands from 1st and 2nd trimester. Design and Setting: Male and female HFA samples from gestational week (GW) 8-19 were examined, including a total of 101 samples from 83 fetuses. Main Outcome Measure(s): Expression level of steroidogenic genes and protein expression/localization were determined by quantitative PCR and immunohistochemistry, respectively, and intra-adrenal steroid levels were quantified by LC-MS/MS. Results: Transcriptional levels of StAR, CYP11A1, CYP17A1, CYP21A2, CYP11B1/2 and SULT2A1 was significantly higher in 2nd trimester compared with 1st trimester (P
Published: 2019

29. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author: Natalia Bogdanova, Karen Carty, Brooke L. Fridley, Argyrios Ziogas, Matthias Dürst, Ignace Vergote, Anxhela Gjyshi, Barry P. Rosen, Heli Nevanlinna, Anna H. Wu, Estrid Høgdall, Sandra Orsulic, Alice W. Lee, Liisa M. Pelttari, Timothy P. Hughes, Francesmary Modugno, Kirsten B. Moysich, Malcolm C. Pike, Xifeng Wu, Anja Rudolph, Philipp Harter, Jolanta Lissowska, Edwin S. Iversen, Susan J. Ramus, Douglas F. Easton, Julie M. Cunningham, Katja K.H. Aben, Liv Cecilie Vestrheim Thomsen, Lynne R. Wilkens, Lene Lundvall, Melissa Buckley, Shelley S. Tworoger, Simon A. Gayther, Allan Jensen, Robert P. Edwards, Angela Brooks-Wilson, Jonathan Tyrer, Rosalind Glasspool, Soo Hwang Teo, Gerhard A. Coetzee, Renato S. Carvalho, Matthew L. Freedman, Jan Lubinski, Diether Lambrechts, Ellen L. Goode, Wei Zheng, Thomas A. Sellers, Y. Ann Chen, Harvey A. Risch, Leon F.A.G. Massuger, Kathryn L. Terry, Beata Spiewankiewicz, Andrew Berchuck, Jennifer A. Doherty, Usha Menon, Christine Walsh, Louise A. Brinton, Hoda Anton-Culver, Alice S. Whittemore, Kunle Odunsi, Linda S. Cook, John R. McLaughlin, Ralf Bützow, Joseph L. Kelley, Fiona Bruinsma, Iwona K. Rzepecka, Jennifer B. Permuth, Dong Liang, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, Marc T. Goodman, Katharina Bischof, Yin Ling Woo, Nicholas T. Woods, Yurii B. Shvetsov, Yu-Tang Gao, Ya Yu Tsai, Andreas du Bois, Aleksandra Gentry-Maharaj, Weiva Sieh, Nadeem Siddiqui, Mary Anne Rossing, Joellen M. Schildkraut, Thilo Dörk, Douglas A. Levine, RL Milne, Lotte Ansgaard Thomsen, Sara H. Olson, Jenny Chang-Claude, Jacek Gronwald, Hannah P. Yang, Peter Hillemanns, Hamed S. Najafabadi, Ed Dicks, Alvaro N.A. Monteiro, Tanja Pejovic, Diana Eccles, Peter A. Fasching, Honglin Song, Hanis Nazihah Hasmad, Beth Y. Karlan, Matthias W. Beckmann, Pamela J. Thompson, Dennis J. Hazelett, Elizabeth M. Poole, Sandrina Lambrechts, Alexander Hein, Gustavo Mendoza-Fandiño, Arif B. Ekici, Kate Lawrenson, Xiao-Ou Shu, Linda E. Kelemen, Elisa V. Bandera, Michelle A.T. Hildebrandt, Clareann H. Bunker, Madalene Earp, Anne M. van Altena, Simon G. Coetzee, Ally Yang, Roberta B. Ness, James Paul, Cezary Cybulski, Valerie McGuire, Line Bjørge, Lara E. Sucheston-Campbell, Ian G. Campbell, Ian McNeish, Shan Wang-Gohrke, Daniel W. Cramer, Paulo C Lyra, Yukie Bean, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Celeste Leigh Pearce, Howard C. Shen, Susanne K. Kjaer, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Graham G. Giles, Irene Orlow, Sean J. Yoder, Reidun K. Kopperud, Jenny Lester, Georgia Chenevix-Trench, Houtan Noushmehr, and Catherine M. Phelan
Subjects: 0301 basic medicine, Cancer Research, Linkage disequilibrium, Cell Cycle Proteins, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Carcinoma, Ovarian Epithelial, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, Genetic Predisposition to Disease, Scaffold/matrix attachment region, Gene, Genotyping, Ovarian Neoplasms, Genetics, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Base Sequence, Chromosome Mapping, DNA, Neoplasm, medicine.disease, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Cystadenocarcinoma, Serous, 3. Good health, DNA-Binding Proteins, HEK293 Cells, 030104 developmental biology, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Female, MAPEAMENTO GENÉTICO, Chromosomes, Human, Pair 9, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
Published: 2019

30. Nodal signaling regulates germ cell development and establishment of seminiferous cords in the human fetal testis

Author: Niels E. Skakkebæk, Signe Perlman, Rod T. Mitchell, Karen R. Kilcoyne, Lene Lundvall, Richard M. Sharpe, Hanne Frederiksen, Anders Juul, Joni Macdonald, Lea Langhoff Thuesen, Anna-Maria Andersson, Anne Jørgensen, John E. Nielsen, Kristine J. Hare, and Ewa Rajpert-De Meyts
Subjects: Male, 0301 basic medicine, EXPRESSION, endocrine system, Nodal Protein, Somatic cell, CARCINOMA-IN-SITU, Nodal signaling, Dioxoles, Biology, General Biochemistry, Genetics and Molecular Biology, TESTICULAR CANCER, 03 medical and health sciences, 0302 clinical medicine, Gonocyte, MARKERS, Pregnancy, Testis, GONADAL DEVELOPMENT, medicine, Humans, XENOGRAFTS, lcsh:QH301-705.5, Testicular cancer, 030219 obstetrics & reproductive medicine, Seminiferous Tubules, medicine.disease, MEIOSIS, Spermatozoa, TUMORS, Activins, Cell biology, Androgen secretion, 030104 developmental biology, medicine.anatomical_structure, DIFFERENTIATION, lcsh:Biology (General), Benzamides, SOMATIC-CELLS, Female, Pregnancy Trimesters, Development of the gonads, NODAL, Germ cell, Signal Transduction
Abstract: Summary: Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. : Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer. Keywords: Nodal, Activin, human fetal testis, testicular germ cell cancer, testicular dysgenesis syndrome, ex vivo culture, xenografting, testicular development, gonocytes, pluripotency factors
Published: 2018

31. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: John McLaughlin, Hanna Yang, Francesmary Modugno, Jennifer B. Permuth, Diana Eccles, Agnieszka Dansonka-Mieszkowska, Matthias W. Beckmann, Elizabeth M. Poole, Pamela J. Thompson, Maria Bisogna, Ellen L. Goode, Michelle A.T. Hildebrandt, Paul D.P. Pharoah, Zhihua Chen, Lambertus A. Kiemeney, Madalene Earp, Claus Høgdall, Jin Q. Cheng, Xifeng Wu, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Stacey J. Winham, Jan Lubinski, Andrew Berchuck, Valerie McGuire, Els Van Niewenhuyse, Arto Leminen, Ralf Bützow, Susan J. Ramus, Angela Brooks-Wilson, Joseph H. Rothstein, Argyrios Ziogas, Ignace Vergote, Ian G. Campbell, Steven A. Narod, Daniel W. Cramer, Simon A. Gayther, Diether Lambrechts, Heli Nevanlinna, Harvey A. Risch, Alice S. Whittemore, Lene Lundvall, Jolanta Lissowska, Kunle Odunsi, Kathryn L. Terry, Y. Ann Chen, Jacek Gronwald, Leon F.A.G. Massuger, Alvaro N.A. Monteiro, Louise A. Brinton, Marc T. Goodman, Celeste Leigh Pearce, Roberta B. Ness, Peter A. Fasching, Joseph L. Kelley, Linda E. Kelemen, Yurii B. Shvetsov, Elisa V. Bandera, Susanne K. Kjaer, Joellen M. Schildkraut, Graham G. Giles, Georgia Chenevix-Trench, Irene Orlow, Weiva Sieh, Liisa M. Pelttari, Catherine M. Phelan, Melissa Moffitt, Brett M. Reid, Jenny Lester, Adriaan Vanderstichele, Linda S. Cook, Usha Menon, Dong Liang, Brooke L. Fridley, Mary Anne Rossing, Julie M. Cunningham, Thilo Dörk, Douglas A. Levine, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Hoda Anton-Culver, Nhu D. Le, Honglin Song, Anna H. Wu, Kirsten B. Moysich, Line Bjørge, Sara H. Olson, Lynne R. Wilkens, Iain A. McNeish, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Natalia Bogdanova, Jennifer A. Doherty, Robert P. Edwards, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, and Estrid Høgdall
Subjects: 0301 basic medicine, RNA editing, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, ovarian cancer risk, Gene expression, Animals, Humans, Gene, Genetic association, Ovarian Neoplasms, Genetics, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Genetic Variation, Middle Aged, 3. Good health, 030104 developmental biology, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Expression quantitative trait loci, ADAR, Female, Disease Susceptibility, polymorphisms, Priority Research Paper
Abstract: RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P
Published: 2016

32. Survival of ovarian cancer patients in Denmark: Results from the Danish gynaecological cancer group (DGCG) database, 1995–2012

Author: Cecilie Dyg Sperling, Mette Calundann Noer, Hellen Mc Kinnon Edwards, Claus Høgdall, Ib Jarle Christensen, Mary Nguyen-Nielsen, and Lene Lundvall
Subjects: Adult, medicine.medical_specialty, Demographics, Denmark, Gynaecological cancer, Danish, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Registries, 030212 general & internal medicine, Mortality, Aged, Ovarian Neoplasms, Gynecology, business.industry, Obstetrics, Mortality rate, Hematology, General Medicine, Middle Aged, medicine.disease, language.human_language, Oncology, 030220 oncology & carcinogenesis, language, Female, business, Ovarian cancer
Abstract: Ovarian cancer has a high mortality rate, especially in Denmark where mortality rates have been reported higher than in adjacent countries with similar demographics. This study therefore examined recent survival and mortality among Danish ovarian cancer patients over an 18-year study period.This nationwide registry-based observational study used data from the Danish Gynecology Cancer Database, Danish Pathology Registry, and Danish National Patient Registry. All patients with ovarian cancer diagnosed between 1995 and 2012 were included in the study. The data sources were linked via the patients' personal identification number and the analyses included data on cancer stage, age, survival, surgery status and comorbidity. The computed outcome measures were age-adjusted mortality rates and age-adjusted overall and relative survival rates for one and five years.We identified 9972 patients diagnosed with ovarian cancer in the period 1995-2012. The absolute one-year mortality rate decreased from 42.8 (CI 40.3-45.6) in 1995-1999 to 28.3 (CI 25.9-30.9) in 2010-2012, and the five-year mortality rate decreased from 28.2 (CI 27.0-29.5) in 1995-1999 to 23.9 (CI 22.9-25.0) in 2005-2009. After stratification by age, comorbidity and cancer stage, the decrease in one-year mortality was most substantial in the 65-74 year old age group 41.1 (CI 38.8-43.5) to 26.5 (CI 24.4-28.7) and for stage III 39.1 (CI 35.1-43.6) to 22.9 (CI 19.9-26.5) and stage IV 91.3 (CI 80.8-103.2) to 41.9 (CI 35.5-49.5). For overall survival, we showed an increase in one-year survival from 68% (CI 66-69%) in 1995-1999 to 76% (CI 74-78%) in 2010-2012 and an increase in five-year survival from 33% (CI 32-35%) in 1995-1999 to 36% (CI 34-38%) in 2005-2009. Relative survival showed similar increases through the period.Ovarian cancer survival in Denmark has improved substantially from 1995 to 2012, bringing Denmark closer to the standards set by adjacent countries.
Published: 2016

33. Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study

Author: Usha Menon, Anna H. Wu, Suzanne C. Dixon, Chiu-Chen Tseng, Dong Liang, Simon A. Gayther, Andrew Berchuck, Peter A. Fasching, Harvey A. Risch, Georgia Chenevix-Trench, Brooke L. Fridley, Joseph L. Kelley, Jennifer A. Doherty, Leon F.A.G. Massuger, Tjoung-Won Park-Simon, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Kenneth D. Swenerton, Jodie N. Painter, Tanja Pejovic, Florian Heitz, Catherine M. Phelan, Beth Y. Karlan, Liisa M. Pelttari, Pamela J. Thompson, Beata Spiewankiewicz, Lene Lundvall, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Liv Cecilie Vestrheim Thomsen, Els Van Nieuwenhuysen, Fiona Bruinsma, Robert P. Edwards, Weiva Sieh, Natalia Bogdanova, Helga B. Salvesen, Diether Lambrechts, Christina M. Nagle, Jolanta Kupryjanczyk, Nicolas Wentzensen, Jacek Gronwald, Alice S. Whittemore, Karen H. Lu, Kunle Odunsi, Line Bjørge, Paul D.P. Pharoah, Kathryn L. Terry, Lambertus A. Kiemeney, Claus Høgdall, Steven A. Narod, Aaron P. Thrift, Diana Eccles, Daniel W. Cramer, Ignace Vergote, Linda S. Cook, Estrid Høgdall, John R. McLaughlin, Malcolm C. Pike, Matthias W. Beckmann, Peter Hillemanns, Anja Rudolph, Roger L. Milne, Maria Bisogna, Sandrina Lambrechts, Ralf Bützow, Francesmary Modugno, Stacey J. Winham, Jan Lubinski, Joseph H. Rothstein, Michelle A.T. Hildebrandt, Heli Nevanlinna, Reidun K. Kopperud, Jolanta Lissowska, Tomasz Huzarski, Arto Leminen, Nadeem Siddiqui, Hannah P. Yang, Graham G. Giles, Janusz Menkiszak, Agnieszka Budzilowska, Louise A. Brinton, Valerie McGuire, Celeste Leigh Pearce, Ian G. Campbell, Hoda Anton-Culver, Kristine G. Wicklund, Susanne K. Kjaer, Marc T. Goodman, Roberta B. Ness, James Paul, Argyrios Ziogas, Linda E. Kelemen, Elisa V. Bandera, Honglin Song, Julie M. Cunningham, Allan Jensen, Nhu D. Le, Wei Zheng, Kirsten B. Moysich, Jonathan Tyrer, Penelope M. Webb, Sara H. Olson, Lynne R. Wilkens, Angela Brooks-Wilson, Xifeng Wu, Rosalind Glasspool, Susan J. Ramus, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, and Ellen L. Goode
Subjects: Oncology, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Genotype, Epidemiology, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Internal medicine, Mendelian randomization, Medicine, Humans, 030212 general & internal medicine, Obesity, Alleles, Aged, 2. Zero hunger, Aged, 80 and over, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Adiposity and Cancer, Cancer, Mendelian Randomization Analysis, General Medicine, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Logistic Models, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Meta-analysis, Multivariate Analysis, Female, business, Body mass index, Genome-Wide Association Study
Abstract: Contains fulltext : 170949.pdf (Publisher’s version ) (Closed access) BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
Published: 2016

34. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Peter Hillemanns, Ralf Bützow, Joseph H. Rothstein, Jennifer A. Doherty, Celeste Leigh Pearce, Louise A. Brinton, Sandra Orsulic, Lene Lundvall, Susanne K. Kjaer, Irene Orlow, Marc T. Goodman, Diether Lambrechts, Agnieszka Podgorska, Kathryn L. Terry, Yukie Bean, Joseph L. Kelley, Jonathan Tyrer, Svend Aage Engelholm, Linda S. Cook, John R. McLaughlin, Melissa Kellar, Graham G. Giles, Shashikant Lele, Anne M. van Altena, Tanja Pejovic, Lotte Nedergaard, Edwin S. Iversen, Robert P. Edwards, Ingvild L. Tangen, Andreas du Bois, Rosalind Glasspool, Florian Heitz, Beth Y. Karlan, Peter A. Fasching, Liisa M. Pelttari, Aleksandra Gentry-Maharaj, Argyrios Ziogas, Pamela J. Thompson, Jenny Chang-Claude, Camilla Krakstad, Andrew Berchuck, Simon A. Gayther, Alice S. Whittemore, Kunle Odunsi, Liv Cecilie Vestrheim Thomsen, Jolanta Kupryjanczyk, Leon F.A.G. Massuger, Nicolas Wentzensen, Karen H. Lu, Alexander Hein, Steven A. Narod, Harvey A. Risch, Francesmary Modugno, Fiona Bruinsma, Joanna Plisiecka-Halasa, Julie M. Cunningham, Sara H. Olson, Linda E. Kelemen, Xifeng Wu, Robert A. Vierkant, Daniel W. Cramer, Yurii B. Shvetsov, Elisa V. Bandera, Arif B. Ekici, Heli Nevanlinna, Lynne R. Wilkens, Jolanta Lissowska, Melissa C. Southey, Shelley S. Tworoger, Allan Jensen, Christine Walsh, Usha Menon, Line Bjørge, Iain A. McNeish, Katja K.H. Aben, Dong Liang, Joellen M. Schildkraut, Ellen L. Goode, Els Van Nieuwenhuysen, Ignace Vergote, Brooke L. Fridley, Weiva Sieh, Anna H. Wu, Thomas A. Sellers, Nhu D. Le, Jacek Gronwald, Anna Jakubowska, Paul D.P. Pharoah, Mary Anne Rossing, Thilo Dörk, Natalia Antonenkova, Lambertus A. Kiemeney, Douglas A. Levine, Cezary Cybulski, Diana Eccles, Hoda Anton-Culver, Matthias W. Beckmann, Valerie McGuire, Elizabeth M. Poole, Claus Høgdall, Ed Dicks, Honglin Song, Sandrina Lambrechts, Ian G. Campbell, Michelle A.T. Hildebrandt, Madalene Earp, Roberta B. Ness, James Paul, Jan Lubinski, Natalia Bogdanova, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Ira Schwaab, Nadeem Siddiqui, Włodzimierz Sawicki, Kirsten B. Moysich, Philipp Harter, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, Rikki Cannioto, Susan J. Ramus, Georgia Chenevix-Trench, Catherine M. Phelan, Sabine Behrens, Jenny Lester, Department of Pathology, Medicum, Clinicum, Department of Obstetrics and Gynecology, Kelemen, Linda E [0000-0003-4362-9784], Hein, Alexander [0000-0003-2601-3398], Behrens, Sabine [0000-0002-9714-104X], Hillemanns, Peter [0000-0001-9829-3531], Nevanlinna, Heli [0000-0002-0916-2976], Kjaer, Susanne K [0000-0002-8347-1398], Jensen, Allan [0000-0001-8124-4880], Cunningham, Julie M [0000-0002-8159-3025], Vierkant, Robert A [0000-0001-6242-5221], Bjorge, Line [0000-0002-0240-2770], Gronwald, Jacek [0000-0002-3643-2871], Brinton, Louise A [0000-0003-3853-8562], Pharoah, Paul DP [0000-0001-8494-732X], Tyrer, Jonathan P [0000-0003-3724-4757], McNeish, Iain [0000-0002-9387-7586], Eccles, Diana [0000-0002-9935-3169], Menon, Usha [0000-0003-3708-1732], Ramus, Susan J [0000-0003-0005-7798], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Ovarian Cancer Association Consortium, consortia, Thymidylate synthase, Ovarian neoplasms, lcsh:Chemistry, 0302 clinical medicine, expression quantitative trait locus, Consortia, Ovarian carcinoma, Odds Ratio, genetics, Expression quantitative trait locus, lcsh:QH301-705.5, Spectroscopy, Single-nucleotide polymorphism, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], biology, GENETIC-VARIATION, General Medicine, Middle Aged, ovarian neoplasms, single-nucleotide polymorphism, Adenocarcinoma, Mucinous, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Computer Science Applications, Gene Expression Regulation, Neoplastic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, DIFFERENT HISTOTYPES, Signal Transduction, Australian Ovarian Cancer Study Group, Risk, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 0699 Other Biological Sciences, Quantitative Trait Loci, 3122 Cancers, thymidylate synthase, Polymorphism, Single Nucleotide, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, 0399 Other Chemical Sciences, medicine, Genetics, CANCER ASSOCIATION CONSORTIUM, Humans, RNA, Antisense, ddc:610, Physical and Theoretical Chemistry, Allele, Molecular Biology, Genetic Association Studies, Hydro-Lyases, METAANALYSIS, 0604 Genetics, Chemical Physics, Organic Chemistry, gynecology, Case-control study, Proteins, Odds ratio, medicine.disease, SYNTHASE MESSENGER-RNA, 030104 developmental biology, Logistic Models, CARBON TRANSFER PATHWAY, lcsh:Biology (General), lcsh:QD1-999, Enolase superfamily member 1, Gynecology, enolase superfamily member 1, Case-Control Studies, Expression quantitative trait loci, biology.protein, 1182 Biochemistry, cell and molecular biology, CIGARETTE-SMOKING, Other Biological Sciences, Other Chemical 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

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

Author: Andreas du Bois, Douglas F. Easton, Aleksandra Gentry-Maharaj, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Anna H. Wu, Jenny Chang-Claude, Jolanta Lissowska, Natalia Antonenkova, Beata Spiewankiewicz, Christine Walsh, Louise A. Brinton, Xifeng Wu, Leon F.A.G. Massuger, Audrey Y. Jung, Nadeem Siddiqui, Jenny Lester, Evelyn Despierre, Rosalind Glasspool, Jacek Gronwald, Claus Høgdall, Ellen L. Goode, Liisa M. Pelttari, Edwin S. Iversen, Alice S. Whittemore, Lynne R. Wilkens, Lene Lundvall, Robert P. Edwards, Natalia Bogdanova, Camilla Krakstad, Kunle Odunsi, Diana Eccles, Katja K.H. Aben, Weiva Sieh, Diether Lambrechts, Simon A. Gayther, Thomas A. Sellers, Satoyo Hosono, Yin Ling Woo, Jolanta Kupryjanczyk, Matthias W. Beckmann, Bu-Tian Ji, Shashi Lele, Pamela J. Thompson, Nicolas Wentzensen, Kirsten B. Moysich, Alice W. Lee, Kathryn L. Terry, Ira Schwaab, Estrid Høgdall, Yurii B. Shvetsov, Francesmary Modugno, Liv Cecilie Vestrheim Thomsen, Elizabeth M. Poole, Xiao-Ou Shu, Michelle A.T. Hildebrandt, Joellen M. Schildkraut, Arif B. Ekici, Hoda Anton-Culver, Philipp Harter, Celeste Leigh Pearce, Kristine G. Wicklund, Georgia Chenevix-Trench, Ralf Bützow, Eva S. Schernhammer, Madalene Earp, Roberta B. Ness, Steven A. Narod, James Paul, Tanja Pejovic, Soo-Hwang Teo, Florian Heitz, Catherine M. Phelan, Stacey J. Winham, Beth Y. Karlan, Susanne K. Kjaer, Sandrina Lambrechts, Jan Lubinski, Irene Orlow, Peter A. Fasching, Valerie McGuire, Lotte Ansgaard Thomsen, Joseph H. Rothstein, Honglin Song, Melissa Kellar, Usha Menon, Alvaro N.A. Monteiro, Ian G. Campbell, Hannah P. Yang, Graham G. Giles, Harvey A. Risch, Shan Wang-Gohrke, Linda E. Kelemen, Andrew Berchuck, Dong Liang, Karen Lu, Elisa V. Bandera, Robert A. Vierkant, John R. McLaughlin, Peter Hillemanns, Alexander Hein, Julie M. Cunningham, Daniel W. Cramer, Yukie Bean, Clareann H. Bunker, Brooke L. Fridley, Jennifer A. Doherty, Mary Anne Rossing, Joe Dennis, Shelley S. Tworoger, Allan Jensen, Thilo Dörk, Douglas A. Levine, Wei Zheng, Yong-Bing Xiang, Matthias Dürst, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Lara E. Sucheston-Campbell, Boon Kiong Lim, Sara H. Olson, Angela Brooks-Wilson, Ingo B. Runnebaum, Zheng Li, Jenny B. Permuth, Roger L. Milne, Barry P. Rosen, Iain A. McNeish, Argyrios Ziogas, Hui Yi Lin, Sandra Orsulic, Nhu D. Le, Malcolm C. Pike, Linda S. Cook, Line Bjørge, Karen Carty, Cezary Cybulski, Ganna Chornokur, Jonathan Tyrer, Susan J. Ramus, Anne M. van Altena, Marc T. Goodman, Ignace Vergote, Ingvild L. Tangen, Department of Pathology, Clinicum, University of Helsinki, Department of Obstetrics and Gynecology, Medicum, Doctoral Programme in Biomedicine, Scott, Rodney John, Dennis, Joe [0000-0003-4591-1214], Bruinsma, Fiona [0000-0002-9356-2015], Cunningham, Julie M [0000-0002-8159-3025], Giles, Graham G [0000-0003-4946-9099], Jakubowska, Anna [0000-0002-5650-0501], Li, Zheng [0000-0002-6141-4990], Sellers, Thomas A [0000-0002-7832-0405], Pharoah, Paul DP [0000-0001-8494-732X], Goode, Ellen L [0000-0002-9094-8326], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Hydrolases, Cell Membranes, Gene Expression, A Kinase Anchor Proteins, lcsh:Medicine, Genome-wide association study, GTPase, Carcinoma, Ovarian Epithelial, Biochemistry, Signaling Molecules, Cell Signaling, Risk Factors, 3123 Gynaecology and paediatrics, Medizinische Fakultät, GTPase Gene, Medicine and Health Sciences, Guanine Nucleotide Exchange Factors, Small GTPase, lcsh:Science, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Invasive Tumors, Genomics, A Kinase Anchor Proteins/genetics, Polymorphism, Single Nucleotide/genetics, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Enzymes, Multidisciplinary Sciences, Carcinoma, Ovarian Epithelial/genetics, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Science & Technology - Other Topics, Female, Guanine nucleotide exchange factor, Cellular Structures and Organelles, Anatomy, TRAITS, Research Article, Signal Transduction, Histology, Genotype, CARCINOMA, General Science & Technology, Rho GTPase-Activating Protein 5, Quantitative Trait Loci, 3122 Cancers, Ras Signaling, Biology, Polymorphism, Single Nucleotide, Monomeric GTP-Binding Proteins/genetics, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, GTP-binding protein regulators, MD Multidisciplinary, Genome-Wide Association Studies, Genetics, Humans, Gene Regulation, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, Rho Guanine Nucleotide Exchange Factors/genetics, Genetic Association Studies, Monomeric GTP-Binding Proteins, Science & Technology, lcsh:R, Biology and Life Sciences, Proteins, Membrane Proteins, Computational Biology, Cancers and Neoplasms, Human Genetics, Cell Biology, Genome Analysis, SUPER-ENHANCERS, Guanosine Triphosphatase, 030104 developmental biology, Cancer research, Enzymology, lcsh:Q, 3111 Biomedicine, Ras superfamily, Quantitative Trait Loci/genetics, Rho Guanine Nucleotide Exchange Factors
Abstract: 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. ispartof: PLOS ONE vol:13 issue:7 ispartof: location:United States status: published
Published: 2018

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

Author: Jolanta Lissowska, Janusz Menkiszak, Louise A. Brinton, Tomasz Huzarski, Sara H. Olson, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Marc T. Goodman, Kenneth D. Swenerton, Susanne K. Kjaer, Rosalind Glasspool, Joseph L. Kelley, Bobbie J. Rimel, Estrid Høgdall, Yurii B. Shvetsov, Argyrios Ziogas, Joellen M. Schildkraut, Jennifer A. Doherty, Weiva Sieh, Christina M. Nagle, Kirsten B. Moysich, Xifeng Wu, Angela Brooks-Wilson, Agnieszka Budzilowska, Roberta B. Ness, James Paul, Jonathan Tyrer, Agnieszka Dansonka-Mieszkowska, Diana Eccles, Philipp Harter, Francesmary Modugno, Melissa C. Southey, Tjoung Won Park-Simon, Penelope M. Webb, Hannah P. Yang, Graham G. Giles, Matthias W. Beckmann, Sandrina Lambrechts, Anna H. Wu, Paul D.P. Pharoah, Lambertus A. Kiemeney, Suzanne C. Dixon-Suen, Valerie McGuire, Maria Bisogna, Ian G. Campbell, Linda E. Kelemen, Andreas du Bois, Aleksandra Gentry-Maharaj, Nhu D. Le, Jenny Chang-Claude, Ellen L. Goode, Els Van Nieuwenhuysen, Robert P. Edwards, Simon A. Gayther, Harvey A. Risch, Line Bjørge, Ignace Vergote, Michelle A.T. Hildebrandt, Ira Schwaab, Arto Leminen, Nadeem Siddiqui, Aaron P. Thrift, Susan J. Ramus, Elisa V. Bandera, Stacey J. Winham, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Brooke L. Fridley, Tanja Pejovic, Florian Heitz, Jolanta Kupryjanczyk, Beth Y. Karlan, Nicolas Wentzensen, Karen H. Lu, Malcolm C. Pike, Claus Høgdall, Linda S. Cook, John R. McLaughlin, Georgia Chenevix-Trench, Peter Hillemanns, Roger L. Milne, Catherine M. Phelan, Sandra Orsulic, Reidun K. Kopperud, Jenny Lester, Alice S. Whittemore, Diether Lambrechts, Kunle Odunsi, Jacek Gronwald, Kathryn L. Terry, Hoda Anton-Culver, Chiu-Chen Tseng, Amanda S. Bruegl, Andrew Berchuck, Lene Lundvall, Ailith Ewing, Ralf Bützow, Peter A. Fasching, Honglin Song, Pamela J. Thompson, Julie M. Cunningham, Joseph H. Rothstein, Allan Jensen, Wei Zheng, Leon F.A.G. Massuger, Audrey Y. Jung, Fiona Bruinsma, Iwona K. Rzepecka, Steven A. Narod, Daniel W. Cramer, Liisa M. Pelttari, Liv Cecilie Vestrheim Thomsen, Usha Menon, Dong Liang, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, and Heli Nevanlinna
Subjects: 0301 basic medicine, Oncology, Adult, Cancer Research, medicine.medical_specialty, Adolescent, Carcinoma, Ovarian Epithelial, Carcinoma, Ovarian Epithelial/epidemiology, Article, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Risk Factors, Internal medicine, Epidemiology of cancer, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Aged, Ovarian Neoplasms, Aged, 80 and over, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Body Height/genetics, Geography, Confounding, Case-control study, Odds ratio, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Body Height, Confidence interval, 3. Good health, 030104 developmental biology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Meta-analysis, Case-Control Studies, Female, Ovarian Neoplasms/epidemiology, Ovarian cancer, Body mass index
Abstract: Background:\ud \ud Observational 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.\ud Methods:\ud \ud We 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.\ud Results:\ud \ud Greater 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.\ud Conclusions:\ud \ud Women 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

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

Author: Ellen L. Goode, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Joe Dennis, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Rosalind Glasspool, Diana Eccles, Susanne K. Kjaer, Roberta B. Ness, James Paul, Matthias Dürst, Camilla Krakstad, Irene Orlow, Rachel Palmieri Weber, Jonathan Tyrer, Valerie McGuire, Matthias W. Beckmann, Thomas A. Sellers, Elizabeth M. Poole, Ian G. Campbell, Arif B. Ekici, Steven A. Narod, Lotte Nedergaard, Shan Wang-Gohrke, Estrid Høgdall, Yurii B. Shvetsov, Douglas F. Easton, Sandrina Lambrechts, Linda E. Kelemen, Zhihua Chen, Karen Lu, Elisa V. Bandera, Qiyuan Li, Joellen M. Schildkraut, Agnieszka Dansonka-Mieszkowska, Liisa M. Pelttari, Kate Lawrenson, Sandra Orsulic, Ed Dicks, Kirsten B. Moysich, Melissa C. Southey, Christine Walsh, Louise A. Brinton, Argyrios Ziogas, Yukie Bean, Julie M. Cunningham, Patricia Harrington, Philipp Harter, Sara H. Olson, Keitaro Matsuo, Alvaro N.A. Monteiro, Claus Høgdall, Anne M. van Altena, Jenny Lester, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Yu-Tang Gao, Shelley S. Tworoger, Maria Bisogna, Michelle A.T. Hildebrandt, Yian Ann Chen, Iain A. McNeish, Allan Jensen, Diether Lambrechts, Usha Menon, Satoyo Hosono, Pamela J. Thompson, Yin Ling Woo, Jennifer Permuth-Wey, Francesmary Modugno, Matthew L. Freedman, Linda S. Cook, Harvey A. Risch, Ya-Yu Tsai, Marc T. Goodman, Dong Liang, Kathryn L. Terry, Soo Hwang Teo, Lara E. Sucheston-Campbell, Ira Schwaab, Robert A. Vierkant, Georgia Chenevix-Trench, Ralf Bützow, Siddhartha Kar, Wei Zheng, Nhu D. Le, Andrew Berchuck, Brooke L. Fridley, Edwin S. Iversen, Robert P. Edwards, Peter Hillemanns, Daniel W. Cramer, Mary Anne Rossing, Thilo Dörk, Malcolm C. Pike, Jolanta Kupryjanczyk, Anja Rudolph, Joseph H. Rothstein, Douglas A. Levine, Xiao-Ou Shu, Nicolas Wentzensen, Hannah P. Yang, Graham G. Giles, Hoda Anton-Culver, Line Bjørge, Peter A. Fasching, Catherine M. Phelan, Simon A. Gayther, Ignace Vergote, Alexander Hein, Cezary Cybulski, Ingvild L. Tangen, Els Van Nieuwenhuysen, Joseph L. Kelley, Honglin Song, Helen Baker, Alice S. Whittemore, Melissa Kellar, Kunle Odunsi, Bu Tian Ji, Heli Nevanlinna, Jolanta Lissowska, Shashi Lele, Barry P. Rosen, Katja K.H. Aben, Karen Carty, Leon F.A.G. Massuger, Iwona K. Rzepecka, Susan J. Ramus, Angela Brooks-Wilson, Xifeng Wu, Ingo B. Runnebaum, Lene Lundvall, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Jan Lubinski, Agnieszka Timorek, Nadeem Siddiqui, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Florian Heitz, Beth Y. Karlan, and Jacek Grownwald
Subjects: endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract: Background: 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. Methods: 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). Results: 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. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2015

38. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Alice S. Whittemore, Kunle Odunsi, Joe Dennis, Usha Menon, Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Melissa C. Southey, Bu-Tian Ji, Y. Ann Chen, Shashi Lele, Dong Liang, Jacek Gronwald, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Andreas du Bois, Diether Lambrechts, Simon A. Gayther, Aleksandra Gentry-Maharaj, Brooke L. Fridley, Boon Kiong Lim, Kathryn L. Terry, Ira Schwaab, Jenny Chang-Claude, Mary Anne Rossing, Thilo Dörk, Kirsten B. Moysich, Satoyo Hosono, Rosalind Glasspool, Camilla Krakstad, Thomas A. Sellers, Douglas A. Levine, Estrid Høgdall, Yurii B. Shvetsov, Joellen M. Schildkraut, Douglas F. Easton, Philipp Harter, Francesmary Modugno, Ellen L. Goode, Karen Carty, John R. McLaughlin, Celeste Leigh Pearce, Alvaro N.A. Monteiro, Yu-Tang Gao, Arto Leminen, Peter A. Fasching, Kristine G. Wicklund, Maria Bisogna, Linda E. Kelemen, Sandrina Lambrechts, Edwin S. Iversen, Jennifer A. Doherty, Karen Lu, Robert P. Edwards, Elisa V. Bandera, Christine Walsh, Liisa M. Pelttari, Fiona Bruinsma, Iwona K. Rzepecka, Michelle A.T. Hildebrandt, Argyrios Ziogas, Soo-Hwang Teo, Susanne K. Kjaer, Lara E. Sucheston-Campbell, Nadeem Siddiqui, Hui-Yi Lin, Linda S. Cook, Julie M. Cunningham, Louise A. Brinton, Shelley S. Tworoger, Allan Jensen, Irene Orlow, Natalia Bogdanova, Helga B. Salvesen, Ralf Bützow, Steven A. Narod, Susan J. Ramus, Xifeng Wu, Anja Rudolph, Jolanta Kupryjanczyk, Nicolas Wentzensen, Clareann H. Bunker, Ganna Chornokur, Ed Dicks, Joseph H. Rothstein, Wei Zheng, Andrew Berchuck, Ignace Vergote, Lynne R. Wilkens, Ingvild L. Tangen, Beata Spiewankiewicz, Alice W. Lee, Yukie Bean, Peter Hillemanns, Lotte Ansgaard Thomsen, Leon F.A.G. Massuger, Valerie McGuire, Diana Eccles, Catherine M. Phelan, Yin Ling Woo, Patricia Harrington, Rachel Palmieri Weber, Evelyn Despierre, Hoda Anton-Culver, Anne M. van Altena, Eva S. Schernhammer, Ernest K. Amankwah, Ian G. Campbell, Jonathan Tyrer, Daniel W. Cramer, Matthias W. Beckmann, Shan Wang-Gohrke, Hannah P. Yang, Graham G. Giles, Lene Lundvall, Ian McNeish, Claus Høgdall, Elizabeth M. Poole, Roger L. Milne, Honglin Song, Hanis Nazihah Hasmad, Jan Lubinski, Ursula Eilber, Jenny Lester, Arif B. Ekici, Pamela J. Thompson, Harvey A. Risch, Kate Lawrenson, Malcolm C. Pike, Jennifer Permuth-Wey, Sandra Orsulic, Roberta B. Ness, James Paul, Robert A. Vierkant, Alexander Hein, Line Bjørge, Zhihua Chen, Marc T. Goodman, Melissa Kellar, Cezary Cybulski, Xiao-Ou Shu, Matthias Dürst, Barry P. Rosen, Heather S.L. Jim, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Nhu D. Le, Heli Nevanlinna, Sara H. Olson, Jolanta Lissowska, and Katja K.H. Aben
Subjects: Oncology, medicine.medical_specialty, education.field_of_study, Epidemiology, Population, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, Biology, medicine.disease, Bioinformatics, Internal medicine, medicine, Carcinoma, Epithelial–mesenchymal transition, Ovarian cancer, Lung cancer, education, Genetics (clinical)
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

39. Ex vivoculture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development

Author: Rod T. Mitchell, Signe Perlman, Anne Jørgensen, Lene Lundvall, John E. Nielsen, Anders Juul, and E. Rajpert-De Meyts
Subjects: Anti-Mullerian Hormone, Male, medicine.medical_specialty, Sex Differentiation, Somatic cell, Granulosa cell, Apoptosis, Tretinoin, SOX9, Biology, Article, COUP Transcription Factor II, Embryo Culture Techniques, Andrology, Fetus, Oogonia, Organ Culture Techniques, Gonocyte, Internal medicine, Testis, medicine, Humans, Proliferation Marker, Cell Proliferation, Granulosa Cells, Cell growth, Ovary, Rehabilitation, Leydig Cells, Obstetrics and Gynecology, Sertoli cell, Immunohistochemistry, Meiosis, Germ Cells, Ki-67 Antigen, Phenotype, Endocrinology, Forkhead box L2, medicine.anatomical_structure, Reproductive Medicine, Oocytes, Female, Signal Transduction, Transcription Factors
Abstract: What are the effects of experimentally manipulating meiosis signalling by addition of retinoic acid (RA) in cultured human fetal gonads?RA-treatment accelerated meiotic entry in cultured fetal ovary samples, while addition of RA resulted in a dysgenetic gonadal phenotype in fetal testis cultures.One of the first manifestations of sex differentiation is the initiation of meiosis in fetal ovaries. In contrast, meiotic entry is actively prevented in the fetal testis at this developmental time-point. It has previously been shown that RA-treatment mediates initiation of meiosis in human fetal ovary ex vivo.This was a controlled ex vivo study of human fetal gonads treated with RA in 'hanging-drop' tissue cultures. The applied experimental set-up preserves germ cell-somatic niche interactions and the investigated outcomes included tissue integrity and morphology, cell proliferation and survival and the expression of markers of meiosis and sex differentiation.Tissue from 24 first trimester human fetuses was included in this study, all from elective terminations at gestational week (GW) 7-12. Gonads were cultured for 2 weeks with and without addition of 1 µM RA. Samples were subsequently formalin-fixed and investigated by immunohistochemistry and cell counting. Proteins investigated and quantified included; octamer-binding transcription factor 4 (OCT4), transcription factor AP-2 gamma (AP2γ) (embryonic germ cell markers), SRY (sex determining region Y)-box 9 (SOX9), anti-Müllerian hormone (AMH) (immature Sertoli cell markers), COUP transcription factor 2 (COUP-TFII) (marker of interstitial cells), forkhead box L2 (FOXL2) (granulosa cell marker), H2A histone family, member X (γH2AX) (meiosis marker), doublesex and mab-3 related transcription factor 1 (DMRT1) (meiosis regulator), cleaved poly ADP ribose polymerase (PARP), cleaved Caspase 3 (apoptosis markers) and Ki-67 antigen (Ki-67) (proliferation marker). Also, proliferation was determined using a 5'-bromo-2'-deoxyuridine (BrdU) incorporation assay.A novel ex vivo 'hanging-drop' culture model for human fetal gonads was successfully established. Continued proliferation of cells without signs of increased apoptosis was observed after 2 weeks of culture. In cultured fetal ovaries treated with RA, an increased number of meiotic germ cells (P0.05) and DMRT1-positive oogonia initiating meiosis (P0.05) was observed, which is in agreement with a previous study. In fetal testes, RA-treatment resulted in a decreased number of gonocytes (P0.05), a reduced percentage of proliferating gonocytes (P0.05), altered expression pattern of the somatic cell markers AMH and COUP-TFII, as well as disrupted seminiferous cord structure and testis morphology.The number of samples included in this study was relatively small due to the limited availability of human fetal tissue.The hanging-drop culture, similarly to other organ culture approaches, allows studies of germ cell-somatic niche interactions and determination of effects after manipulating specific signalling pathways. Our novel finding of disrupted fetal testis development after treatment with RA indicates that abnormal meiosis regulation can potentially cause gonadal dysgenesis. Further studies will elucidate the exact mechanisms and timing of observed effects.This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.Jø. Additional funding for this project was obtained from The Research Council of the Capital Region of Denmark (E.R.-D.M.), The Research Fund at Rigshospitalet (A.Ju. and J.E.N.), Familien Erichssens Fund (A.Jø.), Dagmar Marshalls Fund (A.Jø.) and AaseEjnar Danielsens Fund (A.Jø.). The authors have no conflicts of interest.
Published: 2015

40. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Jenny Lester, Arif B. Ekici, Xiao-Ou Shu, Georgia Chenevix-Trench, Julie M. Cunningham, Catherine M. Phelan, Tassja J. Spindler, Shelley S. Tworoger, Allan Jensen, Diana Eccles, Wei Zheng, Satoyo Hosono, Svend Aage Engelholm, Linda S. Cook, Thomas A. Sellers, John R. McLaughlin, Matthias W. Beckmann, Elizabeth M. Poole, Ignace Vergote, Francesmary Modugno, Jennifer A. Doherty, Sandrina Lambrechts, Lara Sucheston, Wang Gohrke Shan, Rosalind Glasspool, Barry P. Rosen, Pamela J. Thompson, Christine Walsh, Camilla Krakstad, Jennifer Permuth-Wey, Hoda Anton-Culver, Ralf Bützow, Ed Dicks, Yin Ling Woo, Honglin Song, Qiyuan Li, Leon F.A.G. Massuger, Yurii B. Shvetsov, Joellen M. Schildkraut, Xiaoqing Chen, Hannah P. Yang, Graham G. Giles, Sara H. Olson, Edwin S. Iversen, Claus Høgdall, Jacek Grownwald, Fiona Bruinsma, Peter Hillemanns, Iwona K. Rzepecka, Douglas T. Easton, Robert P. Edwards, Lynne R. Wilkens, Yukie Bean, Y. Ann Chen, Jonathan Tyrer, Tanja Pejovic, Patricia Harrington, Iain A. McNeish, Steven A. Narod, Joanna Moes-Sosnowska, Hanis Nazihah Hasmad, Ji-Heui Seo, Line Bjørge, Peter A. Fasching, Daniel W. Cramer, Florian Heitz, Beth Y. Karlan, Cezary Cybulski, Simon A. Gayther, Jolanta Kupryjanczyk, Nhu D. Le, Alexander Hein, Soo Hwang Teo, Nicolas Wentzensen, Valerie McGuire, Michelle A.T. Hildebrandt, Argyrios Ziogas, Heli Nevanlinna, Karen H. Lu, Diether Lambrechts, Kirsten B. Moysich, Jonathan Beesley, Kate Lawrenson, Ian G. Campbell, Andrew Berchuck, Philipp Harter, Lene Lundvall, Sandra Orsulic, Kathryn L. Terry, Jolanta Lissowska, Helen Baker, Matthew L. Freedman, Linda E. Kelemen, Maria Bisogna, Celeste Leigh Pearce, Ira Schwaab, Elisa V. Bandera, Kristine G. Wicklund, Arto Leminen, Nadeem Siddiqui, Joseph H. Rothstein, Melissa Kellar, Matthias Dürst, Harvey A. Risch, Włodzimierz Sawicki, Katja K.H. Aben, Alice S. Whittemore, Kunle Odunsi, Shashi Lele, Noor Azmi Mat Adenan, Susanne K. Kjaer, Robert A. Vierkant, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Anja Rudolph, Els Van Nieuwenhuysen, Irene Orlow, Joe Dennis, Ingvild L. Tangen, Estrid Høgdall, Alice W. Lee, Roberta B. Ness, James Paul, Malcolm C. Pike, Rachel Palmieri Weber, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Natalia Antonenkova, Anne M. van Altena, Xifeng Wu, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Weiva Sieh, Lambertus A. Kiemeney, Lotte Nedergaard, Ursula Eilber, Janet M. Lee, Zhihua Chen, Andreas du Bois, Joseph L. Kelley, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Bu Tian Ji, Liisa M. Pelttari, Usha Menon, Dong Liang, Yu-Tang Gao, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Louise A. Brinton, Marc T. Goodman, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, and Susan J. Ramus
Subjects: Green Fluorescent Proteins, Molecular Sequence Data, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cell Line, Tumor, Ovarian carcinoma, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genetic association, Cell Nucleus, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, medicine.disease, Adenocarcinoma, Mucinous, Neoplasm Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Gene Expression Regulation, Neoplastic, Microscopy, Fluorescence, Chromosomes, Human, Pair 2, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Adenocarcinoma, Female, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

41. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract: The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
Published: 2017

42. Classification of Ovarian Cancer Surgery Facilitates Treatment Decisions in a Gynecological Multidisciplinary Team

Author: Lene Lundvall, Tine H. Schnack, Ib Jarle Christensen, Claus Høgdall, Henrik Lajer, Lotte Nedergaard Thomsen, and Signe Frahm Bjørn
Subjects: Adult, medicine.medical_specialty, Ovarian surgery, Adolescent, Decision Making, Multidisciplinary team, Decision Support Techniques, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gynecologic Surgical Procedures, medicine, Humans, Prospective Studies, Aged, Aged, 80 and over, Ovarian Neoplasms, Patient Care Team, Postoperative Care, 030219 obstetrics & reproductive medicine, business.industry, General surgery, Outcome measures, Obstetrics and Gynecology, Cytoreduction Surgical Procedures, Middle Aged, medicine.disease, Debulking, Predictive value, Surgery, Oncology, 030220 oncology & carcinogenesis, Female, Treatment decision making, Ovarian cancer, business
Abstract: ObjectiveProper planning of intervention and care of ovarian cancer surgery is of outmost importance and involves a wide range of personnel at the departments involved. The aim of this study is to evaluate the introduction of an ovarian surgery classification (COVA) system for facilitating multidisciplinary team (MDT) decisions.Materials and MethodsFour hundred eighteen women diagnosed with ovarian cancers (n = 351) or borderline tumors (n = 66) were selected for primary debulking surgery from January 2008 to July 2013. At an MDT meeting, women were allocated into 3 groups named “pre-COVA” 1 to 3 classifying the expected extent of the primary surgery and need for postoperative care. On the basis of the operative procedures performed, women were allocated into 1 of the 3 corresponding COVA 1 to 3 groups. The outcome measure was the predictive value of the pre-COVA score compared with the actual COVA performed.ResultsThe MDT meeting allocated 213 women (51%) to pre-COVA 1, 136 (33%) to pre-COVA 2, and 52 (12%) to pre-COVA 3. At the end of surgery, 168 (40%) were classified as COVA 1, 158 (38%) were classified as COVA 2, and 28 (7%) were classified as COVA 3. Traced individually, 212 (51%) patients were correctly preclassified at the MDT meeting and distributed into 110 (52%) COVA 1, 71 (52%) COVA 2, and 17 (32%) COVA 3. Analyzing the subgroup of patients with cancer, 164 (47%) were correctly preclassified. Regarding the International Federation of Gynecology and Obstetrics (FIGO) stages, the pre-COVA classification predicted the actual COVA group in 79 (49%) FIGO stages I to IIIB and in 85 (45%) FIGO stages IIIC to IV.ConclusionsThe COVA classification system is a simple and useful tool in the MDT setting where specialists make treatment decisions based on advanced technology. The use of pre-COVA classification facilitates well-organized patient care–relevant procedures to be undertaken. Pre-COVA accurately predicts the final COVA in 51% classified women.
Published: 2017

43. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: Weiva Sieh, Anna H. Wu, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, David Van Den Berg, Joellen M. Schildkraut, Kimberly R. Kalli, Gottfried E. Konecny, Argyrios Ziogas, Usha Menon, Montserrat Garcia-Closas, Anja Rudolph, Jonathan Tyrer, Ann L. Oberg, Alice S. Whittemore, Brooke L. Fridley, Kunle Odunsi, Mary Anne Rossing, Beata Spiewankiewicz, Douglas A. Levine, Jennifer A. Doherty, Peter A. Fasching, Janusz Menkiszak, Matthew J. Maurer, Claus Høgdall, Zachary C. Fogarty, Louise A. Brinton, Galina Lurie, Diether Lambrechts, Allison F. Vitonis, Keith L. Knutson, Diana Eccles, Agnieszka Dansonka-Mieszkowska, Marc T. Goodman, Jenny Lester, Jolanta Kupryjanczyk, Nicolas Wentzensen, Celeste Leigh Pearce, Howard C. Shen, Simon A. Gayther, Kathryn L. Terry, Ira Schwaab, Bridget Charbonneau, Claudia C. Preston, Jan Lubinski, Krista M. Goergen, Georgia Chenevix-Trench, Susanne K. Kjaer, Irene Orlow, Sara H. Olson, Stanley B. Kaye, Matthias W. Beckmann, Daniel W. Cramer, Kate Lawrenson, Matthew S. Block, Paul D.P. Pharoah, Robert A. Vierkant, Chen Wang, Yukie Bean, Laura E. Hays, Sandrina Lambrechts, Catherine M. Phelan, Hoda Anton Culver, Kirsten B. Moysich, Estrid Høgdall, Malcolm C. Pike, Iwona K. Rzepecka, Ignace Vergote, Lara Sucheston, Joseph H. Rothstein, David N. Rider, Christine Walsh, Starr M. Ramirez, Evelyn Despierre, Lene Lundvall, Arif B. Ekici, Cezary Cybulski, Valerie McGuire, Anna deFazio, Ian G. Campbell, Hannah P. Yang, Alexander Hein, Roberta B. Ness, James Paul, Elisa V. Bandera, Jacek Gronwald, Andrew Berchuck, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Lisa E. Paddock, Lynn C. Hartmann, Sharon E. Johnatty, Philipp Harter, James M. Flanagan, Brenda Diergaarde, Julie M. Cunningham, Robert S. Brown, Allan Jensen, Thomas A. Sellers, Honglin Song, Susan J. Ramus, and Petra Seibold
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Immunology, Gene Expression, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, T-Lymphocytes, Regulatory, Article, Internal medicine, Genotype, medicine, Carcinoma, Humans, Mucinous carcinoma, Genetic Predisposition to Disease, Neoplasm Invasiveness, Germ-Line Mutation, Ovarian Neoplasms, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, Genetic Variation, FOXP3, Prognosis, medicine.disease, Patient Outcome Assessment, Clear cell carcinoma, Female, Neoplasm Grading, Ovarian cancer, Clear cell
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
Published: 2014

44. Diagnostic accuracy of risk of malignancy index in predicting complete tumor removal at primary debulking surgery for ovarian cancer patients

Author: Lene Lundvall, Claus Høgdall, Estrid Høgdall, Carsten Lindberg Fagö-Olsen, Sofie Leisby Antonsen, Fanny Håkansson, Svend Aage Engelholm, and Lotte Nedergaard
Subjects: medicine.medical_specialty, Neoplasm, Residual, Risk of malignancy, medicine.medical_treatment, Risk Assessment, medicine, Humans, Aged, Ovarian Neoplasms, Chemotherapy, Receiver operating characteristic, business.industry, Age Factors, Area under the curve, Membrane Proteins, food and beverages, Obstetrics and Gynecology, General Medicine, Middle Aged, medicine.disease, Debulking, Confidence interval, Surgery, ROC Curve, CA-125 Antigen, Female, Tumor removal, Ovarian cancer, business
Abstract: Ovarian cancer patients in whom complete tumor removal is impossible with primary debulking surgery (PDS) may benefit from neoadjuvant chemotherapy and interval debulking surgery. However, the task of performing a pre-operative evaluation of the feasibility of PDS is difficult. We aimed to investigate whether the risk of malignancy index (RMI) was a useful marker for this evaluation. RMI and surgical outcome were investigated in 164 patients, 49 of whom had no residual tumor after PDS. The receiver operating characteristic curve showed an area under the curve of 0.72 (confidence interval: 0.64-0.80). The possibility of complete tumor removal decreased with increasing RMI and there was a tendency towards higher RMI in patients with residual tumor after PDS, but no single cut-off value of RMI produced useful clinical predictive values. In conclusion, RMI alone is not an optimal method to determine whether complete tumor removal is possible with PDS.
Published: 2013

45. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author: Jolanta Kupryjanczyk, Nicolas Wentzensen, Simon A. Gayther, Celeste Leigh Pearce, Susanne K. Kjaer, Irene Orlow, Zachary C. Fogarty, Evelyn Despierre, Yukie Bean, Georgia Chenevix-Trench, Robert A. Vierkant, Agnieszka Dansonka-Mieszkowska, Lene Lundvall, Jonathan Tyrer, Joellen M. Schildkraut, Izabela Ziolkowska-Seta, Diana Eccles, Iwona K. Rzepecka, Catherine M. Phelan, Hoda Anton Culver, Jennifer A. Doherty, Ignace Vergote, Daniel W. Cramer, Matthias W. Beckmann, Susan J. Ramus, Paul D.P. Pharoah, Honglin Song, Ursula Eilber, Galina Lurie, Jan Lubinski, Philipp Harter, Sandrina Lambrechts, David Van DenBerg, James Paul, Ellen L. Goode, Claus Høgdall, Janusz Menkiszak, James M. Flanagan, Christine Walsh, Julie M. Cunningham, Jenny Lester, Kristin L. White, Elisa V. Bandera, Robert S. Brown, Allan Jensen, Stanley B. Kaye, Matthew S. Block, Sharon E. Johnatty, Louise A. Brinton, Estrid Høgdall, Malcolm C. Pike, Thomas A. Sellers, Arif B. Ekici, Andreas du Bois, Hannah P. Yang, Aleksandra Gentry-Maharaj, Cezary Cybulski, Jenny Chang-Claude, Valerie McGuire, Marc T. Goodman, Anna deFazio, Ian G. Campbell, Argyrios Ziogas, Alexander Hein, Lisa E. Paddock, Usha Menon, Brooke L. Fridley, Mary Anne Rossing, Douglas A. Levine, Bridget Charbonneau, Andrew Berchuck, Jacek Gronwald, Alice S. Whittemore, Joseph H. Rothstein, Anja Rudolph, Weiva Sieh, Kimberly R. Kalli, Sara H. Olson, Allison F. Vitonis, Anna H. Wu, Tanja Pejovic, Peter A. Fasching, Florian Heitz, Beth Y. Karlan, Diether Lambrechts, Kathryn L. Terry, Ira Schwaab, and Montserrat Garcia-Closas
Subjects: Oncology, medicine.medical_specialty, Genotype, Epidemiology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, SNP, Humans, Genetic Predisposition to Disease, Survival analysis, Genetic Association Studies, 030304 developmental biology, Genetic association, Proportional Hazards Models, Ovarian Neoplasms, 0303 health sciences, Polymorphism, Genetic, Proportional hazards model, business.industry, Cancer, medicine.disease, Prognosis, Survival Analysis, 3. Good health, 030220 oncology & carcinogenesis, Immunology, Female, business, Ovarian cancer
Abstract: Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.
Published: 2013
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46. Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass

Author: Inga Laursen, Claus Høgdall, Lotte Nedergaard, Anette Tønnes Pedersen, Noreen Sandhu, Lene Lundvall, Ib Jarle Christensen, Dorthe Hartwell, Magnus Christian Lydolph, Estrid Høgdall, Mona Aarenstrup Karlsen, and Svend Aage Engelholm
Subjects: Adult, medicine.medical_specialty, Adolescent, Carcinoma, Ovarian Epithelial, Risk Assessment, Sensitivity and Specificity, Decision Support Techniques, Diagnosis, Differential, Young Adult, WAP Four-Disulfide Core Domain Protein 2, Biomarkers, Tumor, Carcinoma, medicine, Humans, Neoplasms, Glandular and Epithelial, Prospective Studies, Stage (cooking), Young adult, Prospective cohort study, Aged, Pelvic Neoplasms, Aged, 80 and over, Ovarian Neoplasms, Gynecology, business.industry, Membrane Proteins, Proteins, Obstetrics and Gynecology, Middle Aged, medicine.disease, Clinical trial, Oncology, CA-125 Antigen, Biomarker (medicine), Female, business, Risk assessment, Ovarian cancer, Algorithm, Algorithms
Abstract: Objective Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. Methods Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. Results 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). Conclusion HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.
Published: 2012

47. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Francesmary Modugno, Alice S. Whittemore, Kunle Odunsi, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Jolanta Lissowska, Malcolm C. Pike, Bu-Tian Ji, Michelle A.T. Hildebrandt, Warren Davis, Agnieszka Dansonka-Mieszkowska, Line Bjørge, Roberta B. Ness, James Paul, Katja K.H. Aben, Nonna Kolomeyevskaya, Melissa C. Southey, Bridget Kruszka, Daniel W. Cramer, Shashikant Lele, Edwin S. Iversen, Kristina Schmitt, Julie M. Cunningham, Xifeng Wu, Celeste Leigh Pearce, Keitaro Matsuo, Cezary Cybulski, Linda E. Kelemen, Kirsten B. Moysich, Kristine G. Wicklund, Ralf Bützow, Shelley S. Tworoger, Grace Friel, Robert P. Edwards, Agnieszka Timorek, Leah Preus, Anna Jakubowska, Paul D.P. Pharoah, Karen Lu, Lambertus A. Kiemeney, Allan Jensen, Elisa V. Bandera, Steven A. Narod, Soo-Hwang Teo, Susanne K. Kjaer, Jonathan Tyrer, Joseph H. Rothstein, Irene Orlow, Rachel Palmieri Weber, Janine M. Joseph, Anna M. van Altena, Mary Nesline, Rüdiger Klapdor, Hannah P. Yang, Graham G. Giles, Pamela J. Thompson, Christine Walsh, Jolanta Kupryjanczyk, Wei Zheng, Nicolas Wentzensen, Angela Brooks-Wilson, Arto Leminen, Philipp Harter, Nadeem Siddiqui, Joanna Moes-Sosnowska, Yin Ling Woo, Anja Rudolph, John R. McLaughlin, Louise A. Brinton, Ingo B. Runnebaum, Shalaka S. Hampras, Linda S. Cook, Lotte Nedergaard, Lara E. Sucheston-Campbell, Natalia Bogdanova, Alexander Hein, Joseph L. Kelley, Claus Høgdall, Matthias Dürst, Jennifer A. Doherty, Ignace Vergote, Argyrios Ziogas, Ian G. Campbell, Prashant Singh, Hoda Anton-Culver, Shan Wang-Gohrke, Helga B. Salvesen, Stefan Nickels, Ingvild L. Tangen, Joe Dennis, Georgia Chenevix-Trench, Eva S. Schernhammer, Paul K. Wallace, Leon F.A.G. Massuger, Lynne R. Wilkens, Ed Dicks, Yukie Bean, Alice W. Lee, Ian McNeish, Evelyn Despierre, Patricia Harrington, Kevin H. Eng, Maria Bisogna, Nhu D. Le, Sandrina Lambrechts, Andrew Berchuck, Honglin Song, Hanis Nazihah Hasmad, Nils Schoof, Diana Eccles, Harvey A. Risch, Xiao-Ou Shu, Rosalind Glasspool, Peter Hillemanns, Jenny Permuth-Wey, Chi-Chen Hong, Catherine M. Phelan, Marc T. Goodman, Peter A. Fasching, Matthias W. Beckmann, Helen Baker, Doug Easton, Robert A. Vierkant, Barbara Perkins, Lene Lundvall, Elizabeth M. Poole, Joanna Plisiecka-Halasa, Arif B. Ekici, Melissa Kellar, Jan Lubinski, Alyssa Clay, Diether Lambrechts, Jacek Gronwald, Keith L. Knutson, Karen Carty, Camilla Krakstad, Jenny Lester, Simon A. Gayther, Ya-Yu Tsai, Rikki Cannioto, Kathryn L. Terry, Ira Schwaab, Susan J. Ramus, Andreas du Bois, Thomas A. Sellers, Estrid Høgdall, Valeria McGuire, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Sara H. Olson, Ellen L. Goode, Song Liu, Usha Menon, Dong Liang, Tanja Pejovic, Yu-Tang Gao, Florian Heitz, Beth Y. Karlan, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Weiva Sieh, Liisa M. Pelttari, Anna H. Wu, Natalia Antonenkova, Satoyo Hosono, Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Carcinoma, Ovarian Epithelial, T-Lymphocytes, Regulatory, 0302 clinical medicine, STAGE, Gene Frequency, Risk Factors, Genotype, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], immunosuppression, Middle Aged, Protein-Serine-Threonine Kinases, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, Serous fluid, ovarian cancer, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, CARCINOMA, Population, chemical and pharmacologic phenomena, Single-nucleotide polymorphism, FCGR2B, Protein Serine-Threonine Kinases, PERIPHERAL-BLOOD, Biology, DENDRITIC CELLS, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, REGULATORY T-CELLS, education, Aged, Science & Technology, RECEPTOR, Receptor, Transforming Growth Factor-beta Type II, biomarkers, Cell Biology, medicine.disease, 030104 developmental biology, FC-GAMMA-RIIB, Immunology, genetic variation, Cancer research, Ovarian cancer, Receptors, Transforming Growth Factor beta, Clear cell, Priority Research Paper, Adenocarcinoma, Clear Cell
Abstract: Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Published: 2016

48. [The development of a generic guideline for multidisciplinary team conferences in Denmark]

Author: Henrik, Lajer, Jens, Hillingsø, Søren, Høyer, Torben Riis, Rasmussen, Rikke Hjarnø, Hagemann-Madsen, Lone Nørgaard, Petersen, Pernille, Dehn, Michael, Borre, and Lene, Lundvall
Subjects: Patient Care Team, Denmark, Neoplasms, Practice Guidelines as Topic, Critical Pathways, Humans, Interdisciplinary Communication
Abstract: Since 2005 multidisciplinary team conferences (MDT) has been a crucial pivot for the Danish national integrated cancer pathways. Despite the formal decision to implement MDT-conferences, many aspects of this complex organization have never been addressed. In 2014, The Danish Multidisciplinary Cancer Groups (DMCG) provided a workgroup with the task of drafting a Danish national guideline for keeping MDT-conferences. This article presents the process of the workgroup, the background for the final content of the guideline as well as minutes from different parts of the guideline.
Published: 2016

49. European Society of Gynaecologic Oncology Quality Indicators for Advanced Ovarian Cancer Surgery

Author: Carien L. Creutzberg, Lene Lundvall, Ben Davidson, Cristiana Sessa, Ignace Vergote, Andrea Rockall, Christina Fotopoulou, Desmond P. J. Barton, François Planchamp, Silvestro Carinelli, Giovanni Aletti, Luis Chiva, David Cibula, Andreas du Bois, Philippe Morice, Isabelle Ray-Coquard, P. Harter, Christian Marth, Ate G.J. van der Zee, Arash Rafii, Denis Querleu, Institut Bergonié [Bordeaux], UNICANCER, MD Anderson Cancer Center [Madrid, Spain], Imperial College London, The Royal Marsden, Charles University Hospital, Charles University [Prague] (CU), European Institute of Oncology [Milan] (ESMO), Leiden University Medical Center (LUMC), Norwegian Radium Hospital, Kliniken Essen-Mitte, Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Copenhagen = Københavns Universitet (KU), Innsbruck Medical University [Austria] (IMU), Institut Gustave Roussy (IGR), Pôle chirurgical et interventionnel [Gustave Roussy], Weill Cornell Medical College in Qatar (WCMC-Q), Weill Cornell Medicine [Qatar], Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier, Centre Léon Bérard [Lyon], Oncology Institute of Southern Switzerland (IOSI), University Medical Center Groningen [Groningen] (UMCG), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), and Targeted Gynaecologic Oncology (TARGON)
Subjects: Oncology, medicine.medical_specialty, Quality management, media_common.quotation_subject, IMPROVEMENT, [SDV.CAN]Life Sciences [q-bio]/Cancer, Audit, Certification, SURVIVAL IMPACT, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cytoreduction, 03 medical and health sciences, NEOADJUVANT CHEMOTHERAPY, MESH: Gynecologic Surgical Procedures, 0302 clinical medicine, Documentation, Gynecologic Surgical Procedures, COMPLETE CYTOREDUCTION, Ovarian cancer, Internal medicine, Health care, medicine, Operative report, MESH: Quality Indicators, Health Care, Humans, Quality (business), media_common, Quality Indicators, Health Care, Ovarian Neoplasms, 030219 obstetrics & reproductive medicine, MESH: Humans, IV OVARIAN, business.industry, MORTALITY, ADVANCED-STAGE OVARIAN, Obstetrics and Gynecology, CARE, GROSS RESIDUAL DISEASE, Quality assurance, 3. Good health, Surgery, MESH: Ovarian Neoplasms, 030220 oncology & carcinogenesis, Female, PERITONEAL CANCER, business, MESH: Female
Abstract: ObjectivesThe surgical management of advanced ovarian cancer involves complex surgery. Implementation of a quality management program has a major impact on survival. The goal of this work was to develop a list of quality indicators (QIs) for advanced ovarian cancer surgery that can be used to audit and improve the clinical practice. This task has been carried out under the auspices of the European Society of Gynaecologic Oncology (ESGO).MethodsQuality indicators were based on scientific evidence and/or expert consensus. A 4-step evaluation process included a systematic literature search for the identification of potential QIs and the documentation of scientific evidence, physical meetings of an ad hoc multidisciplinarity International Development Group, an internal validation of the targets and scoring system, and an external review process involving physicians and patients.ResultsTen structural, process, or outcome indicators were selected. Quality indicators 1 to 3 are related to achievement of complete cytoreduction, caseload in the center, training, and experience of the surgeon. Quality indicators 4 to 6 are related to the overall management, including active participation to clinical research, decision-making process within a structured multidisciplinary team, and preoperative workup. Quality indicator 7 addresses the high value of adequate perioperative management. Quality indicators 8 to 10 highlight the need of recording pertinent information relevant to improvement of quality. An ESGO-approved template for the operative report has been designed. Quality indicators were described using a structured format specifying what the indicator is measuring, measurability specifications, and targets. Each QI was associated with a score, and an assessment form was built.ConclusionsThe ESGO quality criteria can be used for self-assessment, for institutional or governmental quality assurance programs, and for the certification of centers. Quality indicators and corresponding targets give practitioners and health administrators a quantitative basis for improving care and organizational processes in the surgical management of advanced ovarian cancer.
Published: 2016

50. Udvikling af en generisk vejledning for multidisciplinære team konferencer i Danmark

Author: Henrik Lajer, Jens Hillingsø, Søren Høyer, Torben Riis Rasmussen, Rikke Hjarnø Hagemann-Madsen, Lone Nørgård Petersen, Pernille Dehn, Michael Borre, and Lene Lundvall
Subjects: Journal Article, English Abstract
Abstract: Since 2005 multidisciplinary team conferences (MDT) has been a crucial pivot for the Danish national integrated cancer pathways. Despite the formal decision to implement MDT-conferences, many aspects of this complex organization have never been addressed. In 2014, The Danish Multidisciplinary Cancer Groups (DMCG) provided a workgroup with the task of drafting a Danish national guideline for keeping MDT-conferences. This article presents the process of the workgroup, the background for the final content of the guideline as well as minutes from different parts of the guideline.
Published: 2016

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