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1. New directions in cervical cancer prophylaxis worldwide and in Poland – Case study of the Polish rural female population

Author: Agnieszka Maździarz, Jerzy Wyględowski, Beata Osuch, Beata Jagielska, and Beata Śpiewankiewicz
Subjects: cervical cancer, prophylaxis, screening of cervical cancer, Cytology, Agriculture, Environmental sciences, GE1-350
Abstract: Introduction Cervical cancer is one of the most frequent malignant neoplasms in females. Such neoplasms can be almost completely eliminated by means of adequate primary and secondary prophylaxis. The most developed countries focus their attention on the improvement of prophylaxis systems, test quality, and efficacy improvement, as well as on the expansion of the primary prophylaxis. In Poland, the discussions focus on the improvement of the malfunctioning population programme. Objective Drawing on recent research findings, the article presents current Polish and global recommendations with regard to screening tests for cervical cancer. The results of the Population Programme of Prophylaxis and Early Detection of Cervical Cancer are discussed in the context of current trends of healthy behaviour among women inhabiting rural areas. Description of the state of knowledge In the future, it will be relevant to increase the number of human papillary virus (HPV) tests as part of the prophylaxis programme, especially among the high risk patient group. In particular, there is a necessity to increase the number of vaccinations among young women, especially before the beginning of their sexual activity, as well as to establish new strategies of secondary prophylaxis in this group. At present, women who had been vaccinated should undergo routine screening. In Poland, the report based on SIMP registry (IT System of Prophylaxis Monitoring), shows that only 27% of the 3.3 million of invited women participated in the cytology tests. The data analysis shows that women living in rural areas more often respond and participate in the tests, compared to women living in the cities (39.3% vs. 16.8%).
Published: 2017
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2. 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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3. 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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4. 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

5. 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

6. Data from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
Abstract: Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
Published: 2023

7. Table S1 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
Abstract: Supplementary Table 1 | Gene set for kinome sequencing.
Published: 2023

8. 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

9. Supplementary figures and tables legends from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
Abstract: Legends of supplementary figures and tables
Published: 2023

10. Figure S2 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
Abstract: Supplementary Figure 2 | Significantly mutated genes AKT1, PIK3R1, ERBB3, FBXW7, ATM, CHEK2 and MYO3A. Schematics of the identified novel significantly mutated genes (A) AKT1, (B) PIK3R1, (C) ERBB3, (D) FBXW7, (E) ATM, (F) CHEK2 and (G) MYO3A in OCCC. Mutation marks are shown in black (truncating), red (SIFT and PolyPhen damaging prediction), yellow (SIFT or PolyPhen damaging prediction) or white (SIFT and PolyPhen benign prediction). Mutation effects are indicated with a black spot when paired control was available and written in black (previously described mutation) or red (novel mutations).
Published: 2023

11. 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

12. Supplementary Methods from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Steven de Jong, Ate G.J. van der Zee, René Bernards, Lorenza Mittempergher, Beata Spiewankiewicz, Jolanta Kupryjanczyk, E. Ioana Braicu, James Brenton, Els van Nieuwenhuysen, Ignace Vergote, Helga B. Salvesen, Michael J. Birrer, Anna K.L. Reyners, Roelof J.C. Kluin, Hiroaki Itamochi, Desiree Weening, Evelien W. Duiker, Annemiek M.C. Gennissen, E. Marielle Hijmans, Gert J. Meersma, Harry Klip, Tushar Tomar, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Katrien Berns, and Joseph J. Caumanns
Abstract: Supplementary Methods file
Published: 2023

13. Vulvar sebaceous hyperplasia — a problematic dermatosis of the vulva

Author: Konrad, Gorski, Lidia, Korczynska, Beata, Spiewankiewicz, Krystyna, Swiderska, Monika, Baczkowska, Artur, Skowyra, and Michal, Ciebiera
Subjects: Obstetrics and Gynecology
Abstract: Sebaceous glandular hyperplasia (SGH) is a benign form of skin pathology, occurring in approximately one percent of the population. Risk factors for the SGH include advanced age, male sex, exposure to UV radiation and immunosuppression. The pathogenesis of SGH involves hormonal changes, is also regulated by insulin levels, thyroid stimulating hormone (TSH) and cortisol. SGH manifests itself as solitary or multiple light-yellow lumps, 2-3 mm big, with a smooth surface and a central umbilical depression. The vulvar localization of lesions is extremely rare and presents with a polymorphous clinical picture, posing a major diagnostic problem. A 40-year-old patient presented to the clinic due to vulvar skin lesions, periodically with the swelling of the labia and itching, with the symptoms deteriorating for approximately two years. The patient has been consulted by several doctors; however, the diagnosis has not been established. She did not receive adequate treatment either. On physical examination, attention was drawn to the overgrown labia minora - especially on the right side - with a network of abnormal vessels and numerous small papular lesions. SGH was diagnosed, based on the samples collected from the vulva. The patient was recommended isotretinoin therapy and referred to a dermatologist for a consultation. The presented case of vulvar SGH is interesting and rare. It is a diagnostic challenge with no established treatment standards. Nonetheless, SGH should be considered in the differential diagnosis of vulvar skin lesions. The comprehensive and interdisciplinary care is needed to help patients struggling with this insidious condition.
Published: 2022

14. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Author: Ana Osorio, Fiona Bruinsma, Andrew J. Li, Janine Senz, Stacey J. Winham, Michael E. Carney, Deborah J. Thompson, Xifeng Wu, Susan J. Ramus, Alicia A. Tone, Robert P. Edwards, Chu Chen, Daniel D. Buchanan, Rüdiger Klapdor, Diether Lambrechts, Anthony N. Karnezis, Ralf Bützow, Graham G. Giles, Jolanta Kupryjanczyk, James D. Brenton, Pamela J. Thompson, Joseph L. Kelley, Hui Cai, Dylan M. Glubb, Peter Hillemanns, Veronica Wendy Setiawan, Reidun K. Kopperud, Francesmary Modugno, Rodney J. Scott, Karen H. Lu, Andreas du Bois, Weiva Sieh, Clara Bodelon, Katharina Bischof, Sarah E. Ferguson, Ignace Vergote, Todd L. Edwards, Nadeem Siddiqui, Jennifer A. Doherty, Celeste Leigh Pearce, David G. Huntsman, Håkan Olsson, Ailith Ewing, Tjoung-Won Park-Simon, Harvey A. Risch, Taymaa May, Soo Hwang Teo, Elizabeth G. Holliday, Penelope M. Webb, Lukasz Michael Szafron, Alexander Hein, Martin Köbel, Marjorie J. Riggan, Madhuri Koti, Ahmad Alsulimani, Matthias W. Beckmann, Heli Nevanlinna, Domenico Palli, Melissa C. Larson, Emily White, Ingo B. Runnebaum, Robert A. Vierkant, Elza Khusnutdinova, Jolanta Lissowska, Andrew Berchuck, Rosalind Glasspool, Drakoulis Yannoukakos, Alison M. Dunning, Rosario Tumino, Mia M. Gaudet, Alice S. Whittemore, Anna Jakubowska, Marcus Q. Bernardini, Jennifer B. Permuth, Kunle Odunsi, Aleksandra Gentry-Maharaj, Florentia Fostira, Philipp Harter, Rebecca Sutphen, Sandra Orsulic, Beata Spiewankiewicz, Susanne K. Kjaer, Jessica N. McAlpine, Valerie McGuire, Julie M. Cunningham, Jeffrey Killeen, Christine M. Friedenreich, Estrid Høgdall, George Fountzilas, Michelle A.T. Hildebrandt, Katja K.H. Aben, Tomasz Huzarski, Frédéric Amant, Zhaoming Wang, James M. Flanagan, Timothy R. Rebbeck, Joseph H. Rothstein, Clemens Liebrich, Immaculata De Vivo, Linda Titus, Anna deFazio, Jan Gawełko, Irene Konstantopoulou, Adriaan Vanderstichele, Stephen J. Chanock, Jenny Lester, Amanda B. Spurdle, Allan Jensen, Claus Høgdall, Daniela Annibali, Amalia Mattiello, Peter Kraft, Loic Le Marchand, Line Bjørge, Marina Bermisheva, Agnieszka Podgorska, John Attia, Tracy A. O'Mara, Shashikant Lele, Thomas A. Sellers, Bo Gao, Holly R. Harris, Shan Wang-Gohrke, Lingeng Lu, Louise A. Brinton, Alessandra Macciotta, Digna R. Velez Edwards, Peter A. Fasching, Marc T. Goodman, Linda S. Cook, Constance Turman, Jacek Gronwald, Liv Cecilie Vestrheim Thomsen, Matthias Dürst, Kirsten B. Moysich, Usha Menon, Dong Liang, Arif B. Ekici, Bozena Konopka, Aurelio Barricarte, Thilo Dörk, Stefanie Burghaus, Michael Jones, Loren Lipworth, Zhihua Chen, Xiaoqing Chen, Alison Brand, Iain A. McNeish, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Anthony J. Swerdlow, Anna H. Wu, Obstetrics and Gynaecology, CCA - Cancer biology and immunology, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Quantitative Trait Loci, Genome-wide association study, Biology, Carcinoma, Ovarian Epithelial, Genetic correlation, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Uterine cancer, Risk Factors, Internal medicine, medicine, Humans, Genetic association, Ovarian Neoplasms, Endometrial cancer, Cancer, medicine.disease, 3. Good health, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Human genome, Female, Ovarian cancer, Genome-Wide Association Study
Abstract: Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
Published: 2021

15. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Author: Rosalind A. Eeles, Anne van Altena, Rüdiger Klapdor, Rayjean J. Hung, Graham G. Giles, Ingo B. Runnebaum, Stacey J. Winham, Alicia Beeghly-Fadiel, Michelle A.T. Hildebrandt, Ruea-Yea Huang, Amanda B. Spurdle, Ahmad Alsulimani, Robert Winqvist, Robert J. Hamilton, Clare Turnbull, James M. Flanagan, Jan Gawełko, Kenneth Muir, Peter Kraft, Joseph Vijai, Anna Jakubowska, Paul D.P. Pharoah, Stephen J. Chanock, Ailith Ewing, Mary B. Daly, Artitaya Lophatananon, Arvids Irmejs, Hiltrud Brauch, Paolo Radice, Camilla Krakstad, Liher Imaz, Lambertus A. Kiemeney, Clara Bodelon, Nadeem Siddiqui, Alvaro N.A. Monteiro, Bozena Konopka, Taymaa May, Herbert Yu, Stefanie Burghaus, Michael E. Carney, Siddhartha Kar, Beata Spiewankiewicz, Fernando Moreno Antón, Andreas du Bois, Sune F. Nielsen, Ian Tomlinson, Elza Khusnutdinova, Paolo Peterlongo, Zhihua Chen, Deborah J. Thompson, Agnieszka Podgorski, Päivi Kannisto, Andrew Berchuck, Jenny Chang-Claude, Susan J. Ramus, Florian Heitz, Nawaid Usmani, Tracy A. O'Mara, Joellen M. Schildkraut, Jennifer Permuth, Beth Y. Karlan, Ignace Vergote, Douglas F. Easton, Sara Lindstroem, Agnieszka Mieszkowska, Kirsten B. Moysich, Ana Vega-Gliemmo, Simon A. Gayther, Arif B. Ekici, Lukasz Szafron, Kunle Odunsi, Marjanka K. Schmidt, Harvey A. Risch, Linda J. Titus, Weiva Sieh, Robert A. Vierkant, Davor Lessel, Line Bjørge, Allan Jensen, Wei Zheng, Holly R. Harris, Petra Kleiblova, Peter A. Fasching, Jonathan Tyrer, Iwona K. Rzepecka, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Susanne K. Kjaer, Esther M. John, Daniele Campa, Veronica Wendy Setiawan, Martin Koebel, Cheryl L. Thompson, Håkan Olsson, Dylan M. Glubb, Peter Hillemanns, and Kate Lawrenson
Subjects: Oncology, medicine.medical_specialty, Endometrial cancer, Cancer susceptibility, Susceptibility gene, Effective sample size, Biology, medicine.disease, Genome, medicine.anatomical_structure, Prostate, Internal medicine, medicine, Genetic association
Abstract: We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.
Published: 2020

16. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Author: Clara Bodelon, Anna H. Wu, V. Wendy Setiawan, Jenny Lester, Adriaan Vanderstichele, Daniela Annibali, Michael E. Carney, Jennifer A. Doherty, Shashikant Lele, Jacek Gronwald, Matthias W. Beckmann, George Fountzilas, Christine M. Friedenreich, Heli Nevanlinna, Immaculata De Vivo, Jolanta Lissowska, Soo Hwang Teo, Ahmad Alsulimani, Daniel D. Buchanan, Rosalind Glasspool, Domenico Palli, Madhuri Koti, Katja K.H. Aben, Tanja Pejovic, Linda S. Cook, Line Bjørge, Mia M. Gaudet, Anna Jakubowska, Tomasz Huzarski, Florian Heitz, Beth Y. Karlan, Andreas du Bois, Linda J. Titus, Joseph L. Kelley, Andrew Berchuck, Aleksandra Gentry-Maharaj, Florentia Fostira, Weiva Sieh, Anthony J. Swerdlow, Celeste Leigh Pearce, Constance Turman, Zhaoming Wang, Ignace Vergote, Dylan M. Glubb, Peter Hillemanns, Chu Chen, Tjoung-Won Park-Simon, Andrew J. Li, Susanne K. Kjaer, Jan Gawełko, Stephen J. Chanock, Tracy A. O'Mara, Elizabeth G. Holliday, Jessica N. McAlpine, Ailith Ewing, Amalia Mattiello, Pamela J. Thompson, Xifeng Wu, Alicia A. Tone, Ana Osorio, Fiona Bruinsma, Digna R. Velez Edwards, Janine Senz, Francesmary Modugno, Michael Jones, Sandra Orsulic, Xiaoqing Chen, Todd L. Edwards, Aurelio Barricarte, Hui Cai, Loren Lipworth, David G. Huntsman, Zhihua Chen, Alison M. Dunning, Julie M. Cunningham, Rosario Tumino, Melissa C. Larson, Ralf Bützow, Alison Brand, Allan Jensen, Marina Bermisheva, Reidun K. Kopperud, Beata Spiewankiewicz, Timothy R. Rebbeck, Bozena Konopka, Matthias Dürst, Thomas A. Sellers, Penelope M. Webb, Claus Høgdall, Anthony N. Karnezis, Håkan Olsson, Liv Cecilie Vestrheim Thomsen, Rodney J. Scott, Iain A. McNeish, Arif B. Ekici, Valerie McGuire, Lukasz Szafron, Harvey A. Risch, Bo Gao, Louise A. Brinton, Alessandra Macciotta, Anna deFazio, Rüdiger Klapdor, Graham G. Giles, Usha Menon, Marc T. Goodman, Robert P. Edwards, Robert A. Vierkant, Dong Liang, Shan Wang-Gohrke, Lingeng Lu, Kirsten B. Moysich, Holly R. Harris, Deborah J. Thompson, Jennifer B. Permuth, Alexander Hein, Thilo Dörk, Elza Khusnutdinova, Stefanie Burghaus, Irene Konstantopoulou, Stacey J. Winham, Susan J. Ramus, Agnieszka Podgorska, Rebecca Sutphen, Michelle A.T. Hildebrandt, Jolanta Kupryjanczyk, Ingo B. Runnebaum, James D. Brenton, Karen H. Lu, Katharina Bischof, Nadeem Siddiqui, Drakoulis Yannoukakos, Estrid Høgdall, John Attia, Clemens Liebrich, Loic Le Marchand, Emily White, Amanda B. Spurdle, Peter Kraft, Alice S. Whittemore, Kunle Odunsi, Sarah E. Ferguson, Taymaa May, Marjorie J. Riggan, Philipp Harter, Jeffrey Killeen, James M. Flanagan, Frédéric Amant, Marcus Q. Bernardini, Joseph H. Rothstein, Martin Köbel, Peter A. Fasching, and Diether Lambrechts
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Endometrial cancer, Genome-wide association study, medicine.disease, Genetic correlation, 3. Good health, 03 medical and health sciences, Serous fluid, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, medicine, Epithelial ovarian cancer, business, Clear cell, 030304 developmental biology, Genetic association
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.
Published: 2020
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17. Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author: Helga B. Salvesen, Katrien Berns, James D. Brenton, Joseph J Caumanns, Michael J. Birrer, Tushar Tomar, Els Van Nieuwenhuysen, Rudolf S N Fehrmann, Ignace Vergote, Jolanta Kupryjanczyk, Evelien W. Duiker, Roelof J.C. Kluin, René Bernards, An K.L. Reyners, Gert Jan Meersma, Steven de Jong, Beata Spiewankiewicz, Elena Ioana Braicu, G. Bea A. Wisman, Annemiek M.C. Gennissen, E. Marielle Hijmans, Hiroaki Itamochi, Ate G.J. van der Zee, Harry G. Klip, Desiree Weening, Lorenza Mittempergher, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), de Jong, Steven [0000-0001-5831-6997], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, PHARMACOKINETICS, Cancer Research, Receptor tyrosine kinase, Mice, chemistry.chemical_compound, 0302 clinical medicine, Kinome, Ovarian Neoplasms, biology, Nuclear Proteins, EARLY EVENT, SOLID TUMORS, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, PARP inhibitor, PHASE-II, Heterografts, Female, Erlotinib, Tyrosine kinase, Signal Transduction, medicine.drug, RECURRENT EPITHELIAL OVARIAN, Class I Phosphatidylinositol 3-Kinases, Morpholines, Mechanistic Target of Rapamycin Complex 2, Mechanistic Target of Rapamycin Complex 1, HUMAN CANCERS, Article, Olaparib, 03 medical and health sciences, ErbB, Cell Line, Tumor, medicine, Animals, Humans, PI3K/AKT/mTOR pathway, Cell Proliferation, MUTATIONS, ADENOCARCINOMA, PIK3CA, ARID1A, 030104 developmental biology, chemistry, Mutation, biology.protein, Cancer research, Adenocarcinoma, Clear Cell, Transcription Factors
Abstract: Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models. Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
Published: 2018

18. 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

19. The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome

Author: Agnieszka Podgorska, Agnieszka Timorek, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Beata Spiewankiewicz, Ewa Kwiatkowska, Lukasz Szafron, Anna Stachurska, Barbara Pienkowska-Grela, Martyna Lukasik, Anna Balcerak, Aleksandra Zolocinska, Mona El-Bahrawy, and Bozena Konopka
Subjects: 0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Cyclophosphamide, Genotype, medicine.medical_treatment, Gynecologic oncology, Kaplan-Meier Estimate, Polymorphism, Single Nucleotide, Disease-Free Survival, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, DNA-damaging chemotherapy, CEBPA, Antineoplastic Combined Chemotherapy Protocols, medicine, synonymous polymorphism, Humans, Genotyping, Aged, Proportional Hazards Models, Gynecology, Ovarian Neoplasms, Chemotherapy, Taxane, business.industry, Middle Aged, medicine.disease, Prognosis, Chemotherapy regimen, 030104 developmental biology, ovarian cancer, Treatment Outcome, 030220 oncology & carcinogenesis, gene expression, CCAAT-Enhancer-Binding Proteins, Female, business, Ovarian cancer, medicine.drug, Research Paper
Abstract: // Bozena Konopka 1, * , Lukasz Michal Szafron 1, * , Ewa Kwiatkowska 2 , Agnieszka Podgorska 1 , Aleksandra Zolocinska 3 , Barbara Pienkowska-Grela 1 , Agnieszka Dansonka-Mieszkowska 1 , Anna Balcerak 3 , Martyna Lukasik 1 , Anna Stachurska 1, 4 , Agnieszka Timorek 5 , Beata Spiewankiewicz 6 , Mona El-Bahrawy 7 , Jolanta Kupryjanczyk 1 1 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 2 Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 3 Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 4 Department of Applied Pharmacy and Bioengineering, Medical University of Warsaw, Warsaw, Poland 5 Department of Obstetrics, Gynecology and Oncology, 2nd Faculty of Medicine, Medical University of Warsaw and Brodnowski Hospital, Warsaw, Poland 6 Department of Gynecologic Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 7 Department of Histopathology, Imperial College London, UK * These authors have contributed equally to this study Correspondence to: Lukasz Michal Szafron, email: lukszafron@gmail.com Keywords: ovarian cancer, CEBPA, synonymous polymorphism, gene expression, DNA-damaging chemotherapy Received: May 18, 2016 Accepted: August 25, 2016 Published: September 02, 2016 ABSTRACT The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (p T, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy.
Published: 2016

20. 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

21. 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

22. 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

23. Anti Adeno-Associated Virus 2 (AAV) Antibody Profile in Ovarian Cancer Ascitic Fluid: Implications for AAV Intraperitoneal Gene Therapy

Author: Joanna Skubis Zegadło, Magdalena Kowalska, Beata Spiewankiewicz, Wacław Smiertka, Krzysztof Gawrychowski, and Maciej Małecki
Subjects: biology, business.industry, viruses, Genetic enhancement, medicine.disease_cause, medicine.disease, Virology, Neutralization, Virus, law.invention, Transduction (genetics), law, Immunology, Recombinant DNA, biology.protein, Medicine, Antibody, business, Ovarian cancer, Adeno-associated virus
Abstract: Objective: Recombinant adeno-associated virus (rAAV) type 2 is a common vector used in gene therapy. However, the presence of anti-AAV2 neutralizing antibodies or other neutralizing factors can significantly limit effective transduction. Intraperitoneal gene therapy could enable local delivery of the target gene directly to ovarian cancer cells. Until now, there have been no reports on the presence of anti-AAV antibodies in ascitic fluid, which might limit the effectiveness of rAAV as a candidate vector for intraperitoneal gene therapy. Thus, the characterization of the preexisting neutralization antibodies in ascitic fluid will provide insight into successful intraperitoneal gene therapy. Methods: The study was conducted on 23 ascitic fluid samples obtained from women with stage 3 and 4 ovarian cancer. The samples were collected to determine the presence of anti-AAV antibodies with ELISA test and the presence of neutralizing antibodies with neutralizing assay. Results: Our results indicate that anti-rAAV antibodies are present in 70%, whereas neutralizing factors/antibodies are present in 78% of analyzed ascitic fluid samples. This correlation provides evidence for the presence of additional, different from antibodies, currently unknown factors in ascites, which are able to inhibit AAV2 infection in the absence of anti-AAV antibodies. Conclusion: The presence of neutralizing antibodies against rAAV or other neutralizing factors in ascitic fluid should be taken into account during intraperitoneal gene therapy, because they might limit effective intraperitoneal gene therapy with rAAV as a vector.
Published: 2017

24. Pregnancy following breast cancer

Author: Beata Spiewankiewicz, Anna Skrzypczyk-Ostaszewicz, Beata Jagielska, Dominika Jaxa-Larecka, and Agnieszka Maździarz
Subjects: Oncology, medicine.medical_specialty, Pregnancy, Breast cancer, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, medicine, Obstetrics and Gynecology, Estrogen receptor, medicine.disease, business
Published: 2014

25. Breast cancer in pregnancy

Author: Beata Osuch, Beata Jagielska, Anna Skrzypczyk-Ostaszewicz, and Beata Spiewankiewicz
Subjects: Pregnancy, medicine.medical_specialty, Breast cancer, Oncology, business.industry, Obstetrics, Endocrinology, Diabetes and Metabolism, medicine, Obstetrics and Gynecology, medicine.disease, business
Published: 2014

26. 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

27. Ovarian small cell carcinoma of hypercalcemic type – evidence of germline origin and smarca4 gene inactivation. a pilot study

Author: Iwona K. Rzepecka, Beata Spiewankiewicz, Agnieszka Podgorska, Joanna Plisiecka-Halasa, Agnieszka Dansonka-Mieszkowska, Alina Rembiszewska, Agnieszka Budzilowska, Bozena Konopka, Joanna Moes-Sosnowska, Jolanta Kupryjanczyk, Lukasz Szafron, and W Grajkowska
Subjects: Adult, Oncology, medicine.medical_specialty, Population, Pilot Projects, Biology, Histogenesis, Pathology and Forensic Medicine, Diagnosis, Differential, Pregnancy, Internal medicine, Biomarkers, Tumor, Carcinoma, medicine, Humans, Gene Silencing, Prospective Studies, Carcinoma, Small Cell, education, Germ-Line Mutation, Rhabdoid Tumor, Ovarian Neoplasms, education.field_of_study, DNA Helicases, Teratoma, Nuclear Proteins, DNA, Neoplasm, Sequence Analysis, DNA, General Medicine, medicine.disease, Ovarian Small Cell Carcinoma, Primary tumor, Gene Expression Regulation, Neoplastic, Atypical teratoid rhabdoid tumor, Cancer research, Female, Immature teratoma, Transcription Factors
Abstract: Ovarian tumors from two patients, compatible by histological and immunohistochemical criteria with small cell carcinoma of hypercalcemic type (SCCHT) (WT1+, EMA dispersed+, synaptophysin+ or dispersed+), were extensively sampled in order to find clues to their histogenesis. Subsequently, small foci of immature teratoma were found in both of them (in 1/122 and in 3/80 tumor sections). In one case, microfoci of yolk sac tumor were also present within the teratoma area as well as in the background of the small cell tumor population - in the primary tumor and in omental metastasis. We found a resemblance of the microscopic patterns of SCCHT and atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system, and this prompted us to evaluate INI-1 and SMARCA4 immunohistochemical expression, because their alternative loss is regarded as a molecular hallmark of AT/RT. INI-1 expression was retained, while that of SMARCA4 was lost. We therefore analyzed tumor DNA by PCR amplification and sequencing for mutations in the SMARCA4 gene (NG_011556.1), which were identified in both tumors (c.2184_2206del; nonsense c.3277C>T - both in one tumor; nonsense c.3760G>T in another tumor). These data suggest that SCCHT is most likely an embryonal tumor originating from immature teratoma and related to malignant rhabdoid tumor. Further analyses are necessary to determine whether the tumors diagnosed as SCCHT constitute a homogeneous group or represent more than one entity.
Published: 2013

28. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Author: Steven A. Narod, Beata Spiewankiewicz, Usha Menon, Tanja Pejovic, Dong Liang, Lynne R. Wilkens, Diana Eccles, Claus Høgdall, Florian Heitz, Beth Y. Karlan, John R. McLaughlin, Xiao-Ou Shu, Jennifer A. Doherty, Marc T. Goodman, Yu-Tang Gao, Brooke L. Fridley, Matthias W. Beckmann, Satoyo Hosono, Mary Anne Rossing, Elizabeth M. Poole, Thilo Dörk, Roger L. Milne, Douglas A. Levine, Arif B. Ekici, Francesmary Modugno, Hanis Nazihah Hasmad, Evelyn Despierre, Harvey A. Risch, Michelle A.T. Hildebrandt, Jenny Lester, Argyrios Ziogas, Arto Leminen, Sara H. Olson, Kate Lawrenson, Sandra Orsulic, Nadeem Siddiqui, Weiva Sieh, Ganna Chornokur, Ernest K. Amankwah, Natalia Bogdanova, Liisa M. Pelttari, Nhu D. Le, Lene Lundvall, Kirsten B. Moysich, Robert A. Vierkant, Helga B. Salvesen, Douglas F. Easton, Yin Ling Woo, Lotte Ansgaard Thomsen, Boon Kiong Lim, Philipp Harter, Hannah P. Yang, Graham G. Giles, Andrew Berchuck, Heather S.L. Jim, Anna H. Wu, Christine Walsh, Zhihua Chen, Alice S. Whittemore, Louise A. Brinton, Anne M. van Altena, Alice W. Lee, Fiona Bruinsma, Iwona K. Rzepecka, Natalia Antonenkova, Melissa Kellar, Jonathan Tyrer, Peter Hillemanns, Kunle Odunsi, Joe Dennis, Heli Nevanlinna, Alexander Hein, Catherine M. Phelan, Xifeng Wu, Jolanta Lissowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Roberta B. Ness, James Paul, Linda S. Cook, Jacek Gronwald, Katja K.H. Aben, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Linda E. Kelemen, Sandrina Lambrechts, Jan Lubinski, Leon F.A.G. Massuger, Karen Carty, Matthias Dürst, Ursula Eilber, Simon A. Gayther, Karen Lu, Bu-Tian Ji, Elisa V. Bandera, Shashi Lele, Keitaro Matsuo, Maria Bisogna, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Susan J. Ramus, Alvaro N.A. Monteiro, Edwin S. Iversen, Robert P. Edwards, Diether Lambrechts, Ellen L. Goode, Pamela J. Thompson, Ralf Bützow, Clareann H. Bunker, Jennifer Permuth-Wey, Anja Rudolph, Joseph H. Rothstein, Kathryn L. Terry, Ira Schwaab, Andreas du Bois, Aleksandra Gentry-Maharaj, Jolanta Kupryjanczyk, Nicolas Wentzensen, Ignace Vergote, Valerie McGuire, Jenny Chang-Claude, Ingvild L. Tangen, Ian G. Campbell, Daniel W. Cramer, Shan Wang-Gohrke, Peter A. Fasching, Rosalind Glasspool, Camilla Krakstad, Hoda Anton-Culver, Eva S. Schernhammer, Thomas A. Sellers, Lara E. Sucheston-Campbell, Estrid Høgdall, Yurii B. Shvetsov, Joellen M. Schildkraut, Honglin Song, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Ian McNeish, Wei Zheng, Barry P. Rosen, Malcolm C. Pike, Line Bjørge, Cezary Cybulski, Celeste Leigh Pearce, Kristine G. Wicklund, Soo-Hwang Teo, Susanne K. Kjaer, Hui-Yi Lin, Irene Orlow, Yukie Bean, Ann Y. Chen, and Rachel Palmieri Weber
Subjects: endocrine system, 0303 health sciences, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, medicine.disease, Bioinformatics, Article, 03 medical and health sciences, PER3, 0302 clinical medicine, CSNK1E, 030220 oncology & carcinogenesis, Genotype, Genetic variation, Cancer research, medicine, Circadian rhythm, Ovarian cancer, Ovulation, 030304 developmental biology, media_common
Abstract: Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. ispartof: Journal of Genetics and Genome Research vol:2 issue:2 pages:017- ispartof: location:United States status: published
Published: 2015

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

Author: Ernest K, Amankwah, Hui-Yi, Lin, Jonathan P, Tyrer, Kate, Lawrenson, Joe, Dennis, Ganna, Chornokur, 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, Zhihua, Chen, Y Ann, Chen, 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, Hanis N, Hasmad, Alexander, Hein, Florian, Heitz, Michelle A T, Hildebrandt, Peter, Hillemanns, Claus K, Hogdall, Estrid, Hogdall, Satoyo, Hosono, Edwin S, Iversen, Anna, Jakubowska, Allan, Jensen, Bu-Tian, Ji, Beth Y, Karlan, Heather, Jim, Melissa, 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, Ian, 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, Jennifer, Permuth-Wey, 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-Campbell, 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, Linda E, Kelemen, Andrew, Berchuck, 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: Adult, Ovarian Neoplasms, Risk, Epithelial-Mesenchymal Transition, Genotype, Carcinoma, Ovarian Epithelial, Middle Aged, Polymorphism, Single Nucleotide, White People, Article, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Aged, Genome-Wide Association Study
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 (P0.05) 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-value0.05 and a false discovery rate (FDR)0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
Published: 2015

30. Clinical value of human epididymis protein 4 and the Risk of Ovarian Malignancy Algorithm in differentiating borderline pelvic tumors from epithelial ovarian cancer in early stages

Author: Malgorzata Fuksiewicz, Maciej Skrzypczak, Beata Kotowicz, Joanna Jonska-Gmyrek, Piotr Sobiczewski, Maria Kowalska, and Beata Spiewankiewicz
Subjects: Adult, Cystadenofibroma, Adolescent, Carcinoma, Ovarian Epithelial, Disease-Free Survival, Diagnosis, Differential, Young Adult, WAP Four-Disulfide Core Domain Protein 2, Risk Factors, Biomarkers, Tumor, Medicine, Humans, Epithelial ovarian cancer, Neoplasms, Glandular and Epithelial, Young adult, Ovarian malignancy, Aged, Neoplasm Staging, Proportional Hazards Models, Aged, 80 and over, Ovarian Neoplasms, business.industry, Proportional hazards model, Obstetrics and Gynecology, Membrane Proteins, Proteins, Middle Aged, medicine.disease, Epididymis, medicine.anatomical_structure, Reproductive Medicine, ROC Curve, Area Under Curve, CA-125 Antigen, Female, Differential diagnosis, business, Ovarian cancer, Algorithm, Algorithms
Abstract: The clinical value of human epididymis protein 4 (HE4) and the possibility of its use in the differential diagnosis in patients with benign, borderline and epithelial ovarian cancer in early International Federation of Gynaecology and Obstetrics (FIGO) stages.The study group consisted of 205 women, including 60 with ovarian cancer, 18 with borderline tumors, 77 with benign lesions and 50 healthy subjects. In all the patients, before the treatment and in control groups, we determined CA 125 and HE4 in serum by electrochemiluminescence on the basis of the COBAS e601 system. For comparison of two independent groups, we used the U Mann-Whitney test. The analysis of the diagnostic power of the assessed parameters has been determined using the MedCalc statistical program. The probability of disease free survival (DFS) was evaluated using the log-rank test and Cox regression model.Concentrations of HE4, CA 125 and Risk of Ovarian Malignancy Algorithm (ROMA) value were significantly higher in early ovarian cancer than in patients with benign (P0.0001) and borderline tumors (P0.002), the receiver operating characteristics (ROC) curves, demonstrated the highest diagnostic sensitivity for the ROMA score, as well post (AUC=0.817) as pre-menopausal (AUC=0.806). HE4 concentrations (P0.021) and the value of the ROMA score (P0.004) were significantly higher in patients with relapse than in patients in remission. There was no connection between concentrations of the studied tumor markers and DFS.Determination of HE4 serum concentrations has a significant clinical value, especially in patients with benign lesions and elevated CA 125 levels. The combined assessment of HE4, CA 125 and the ROMA algorithm is helpful in differentiating benign tumors and borderline pelvic tumors from epithelial ovarian cancer in early FIGO stages. Determination of HE4, CA 125 and ROMA algorithm is not helpful in differentiating patients with borderline from benign lesions.
Published: 2015

31. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study

Author: Linda E. Kelemen, Argyrios Ziogas, Celeste Leigh Pearce, Karen Lu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Elisa V. Bandera, Hoda Anton-Culver, Nadeem Siddiqui, Kristine G. Wicklund, Hannah P. Yang, Graham G. Giles, Georgia Chenevix-Trench, Anna Jakubowska, Paul D.P. Pharoah, Susanne K. Kjaer, Jonathan Tyrer, Catherine M. Phelan, Honglin Song, Lambertus A. Kiemeney, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Irene Orlow, Natalia Bogdanova, Helga B. Salvesen, Lara E. Sucheston-Campbell, Liisa M. Pelttari, Alexander Hein, Jenny Lester, Lynne R. Wilkens, Alice W. Lee, Valerie McGuire, Yukie Bean, Julie M. Cunningham, Diana Eccles, Rosalind Glasspool, Patricia Harrington, Shelley S. Tworoger, Joseph H. Rothstein, Allan Jensen, Rachel Palmieri Weber, Ian G. Campbell, Nhu D. Le, Matthias W. Beckmann, Marc T. Goodman, Sandra Orsulic, Shan Wang-Gohrke, Elizabeth M. Poole, Usha Menon, Harvey A. Risch, Anja Rudolph, Tanja Pejovic, Lotte Nedergaard, Dong Liang, Jan Lubinski, Els Van Nieuwenhuysen, Arif B. Ekici, Camilla Krakstad, Ignace Vergote, Robert A. Vierkant, Ingvild L. Tangen, Ursula Eilber, Florian Heitz, Beth Y. Karlan, Diether Lambrechts, Brooke L. Fridley, Malcolm C. Pike, Anne M. van Altena, Alice S. Whittemore, Estrid Høgdall, Kunle Odunsi, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Yurii B. Shvetsov, Joellen M. Schildkraut, Daniel O. Stram, Francesmary Modugno, Melissa Kellar, Christine Walsh, Roberta B. Ness, James Paul, Line Bjørge, Edwin S. Iversen, Robert P. Edwards, Louise A. Brinton, Joanna Plisiecka-Halasa, Anna H. Wu, Linda S. Cook, Joseph L. Kelley, Jolanta Kupryjanczyk, Nicolas Wentzensen, Matthias Dürst, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Cezary Cybulski, Douglas A. Stram, Michelle A.T. Hildebrandt, Weiva Sieh, Kathryn L. Terry, Ira Schwaab, Sara H. Olson, Iain A. McNeish, Ellen L. Goode, Heli Nevanlinna, Maria Bisogna, Jolanta Lissowska, Katja K.H. Aben, Leon F.A.G. Massuger, Beata Spiewankiewicz, Peter A. Fasching, Fiona Bruinsma, Claus Høgdall, Kirsten B. Moysich, Philipp Harter, Jacek Gronwald, Xifeng Wu, Lene Lundvall, Andrew Berchuck, Peter Hillemanns, Pamela J. Thompson, Karen Carty, Susan J. Ramus, Emily Myers, Angela Brooks-Wilson, Ingo B. Runnebaum, and Daniel W. Cramer
Subjects: Candidate gene, Aging, Genome-wide association study, Bioinformatics, Gene, FSHB, Risk Factors, Genotype, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Tumor, Obstetrics and Gynecology, Single Nucleotide, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Signal Transduction, Biotechnology, Australian Ovarian Cancer Study Group, Genetic Markers, endocrine system, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, Rare Diseases, Ovarian cancer, Australian Cancer Study, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetic variation, Oncology & Carcinogenesis, Polymorphism, Prevention, Human Genome, Case-control study, medicine.disease, INHBB, Logistic Models, Case-Control Studies, Polymorphisms, Gonadotropins, Biomarkers, Genome-Wide Association Study
Abstract: Contains fulltext : 155211.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Published: 2015

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

Author: Francois Bacot, Julie M. Cunningham, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Anja Rudolph, Jonathan Tyrer, Edwin S. Iversen, Tanja Pejovic, Lynne R. Wilkens, Sebastian M. Armasu, Alice S. Whittemore, Florian Heitz, Beth Y. Karlan, Yin Ling Woo, Karen Lu, Heather S. L. Jim, Bohdan Górski, Wei Zheng, Harvey A. Risch, Hui-Yi Lin, Arif B. Ekici, Rosalind Glasspool, Kimberly R. Kalli, Diether Lambrechts, Nathan Lee, Toru Nakanishi, Diana Eccles, Gottfried E. Konecny, Ian G. Campbell, Heli Nevanlinna, Thomas A. Sellers, Jin Q. Cheng, Agnieszka Dansonka-Mieszkowska, Argyrios Ziogas, Matthias W. Beckmann, Michael J. Birrer, Melissa C. Southey, Liisa M. Pelttari, Jolanta Kupryjanczyk, Camilla Krakstad, Elizabeth M. Poole, Robert A. Vierkant, Xiao-Ou Shu, Nicolas Wentzensen, Fumitaka Kikkawa, Y. Ann Chen, Celeste Leigh Pearce, Howard C. Shen, Allison F. Vitonis, Ya-Yu Tsai, Gerhard A. Coetzee, Jolanta Lissowska, Sandrina Lambrechts, Dong Liang, Kathryn L. Terry, Hannah P. Yang, Graham G. Giles, Daniel C. Tessier, Ira Schwaab, Anna H. Wu, Hoda Anton-Culver, Gianluca Severi, Stephen J. Chanock, Douglas F. Easton, Weiva Sieh, Natalia Antonenkova, Anne M. van Altena, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Qiuyin Cai, Susanne K. Kjaer, Katja K.H. Aben, Kirsten B. Moysich, Estrid Høgdall, Ellen L. Goode, Lambertus A. Kiemeney, David Fenstermacher, Xiaotao Qu, Jesus Gonzalez-Bosquet, Daniel O. Stram, Irene Orlow, Joellen M. Schildkraut, Antonis C. Antoniou, Rachel Palmieri Weber, Satoyo Hosono, Jie Lin, Roberta B. Ness, Shan Wang-Gohrke, Simon A. Gayther, James Paul, Jill S. Barnholtz-Sloan, Usha Menon, Johnathan M. Lancaster, Jennifer A. Doherty, Stefan Nickels, Paola Raska, Jan Lubinski, Boon Kiong Lim, Elisabeth Wik, Aleksandra Gentry-Maharaj, Kate Lawrenson, Georgia Chenevix-Trench, Maureen E. Hoatlin, Stanley B. Kaye, Lotte Nedergaard, Natalia Bogdanova, Zhihua Chen, Janet M. Lee, Laura Baglietto, Francesmary Modugno, Linda E. Kelemen, Elisa V. Bandera, Montserrat Garcia-Closas, Helga B. Salvesen, Brooke L. Fridley, Rod Karevan, Houtan Noushmehr, Thilo Dörk, Ralf Bützow, Nhu D. Le, Douglas A. Levine, Sara H. Olson, Mine S. Cicek, Louise A. Brinton, Soo-Hwang Teo, Ignace Vergote, Pamela J. Thompson, Catherine M. Phelan, Marc T. Goodman, Linda S. Cook, Matthias Dürst, Malcolm C. Pike, Boris Winterhoff, Mari K. Halle, Andreas du Bois, Daniel Vincent, Valerie McGuire, Rebecca Sutphen, Peter A. Fasching, Jenny Chang-Claude, Stefan P. Renner, Jennifer Permuth-Wey, Aneliya Velkova, John McLaughlin, Kunle Odunsi, Greg Bloom, Leon F.A.G. Massuger, Arto Leminen, Melissa C. Larson, Iwona K. Rzepecka, Philipp Harter, Beata Spiewankiewicz, Mary Anne Rossing, Jacek Gronwald, Yurii B. Shvetsov, Claus Høgdall, Martin Gore, Angela Brooks-Wilson, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Ingo B. Runnebaum, James M. Flanagan, Galina Lurie, Alvaro N.A. Monteiro, Per Hall, Andrew Berchuck, Robert Edwards, Yong-Bing Xiang, Honglin Song, Susan J. Ramus, Famida Zulkifli, Lorna Rodriguez-Rodriguez, Steven A. Narod, Daniel W. Cramer, and Cancer Research UK
Subjects: Genetics and Molecular Biology (all), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Australian Ovarian Cancer Study, Aetiology, screening and detection [ONCOL 5], Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 17, Genetic Predisposition to Disease, Chemistry (all), Biochemistry, Genetics and Molecular Biology (all), Physics and Astronomy (all), Carcinoma, Ovarian Epithelial, SITE POLYMORPHISMS, Biochemistry, 0302 clinical medicine, Polymorphism (computer science), Neoplasms, Ovarian Epithelial, Consortium of Investigators of Modifiers of BRCA1/2, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Midical sciences: 700::Clinical medical sciences: 750::Gynaecology and obstetrics: 756 [VDP], RISK, 0303 health sciences, COMMON INVERSION, Multidisciplinary, Glandular and Epithelial, Single Nucleotide, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Multidisciplinary Sciences, GENÉTICA, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, FUNCTIONAL ANNOTATION, Human, Biotechnology, Biology, Medisinske fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756 [VDP], BINDING-SITES, General Biochemistry, Genetics and Molecular Biology, Article, Chromosomes, 03 medical and health sciences, Rare Diseases, Translational research [ONCOL 3], Australian Cancer Study, MD Multidisciplinary, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, PARKINSON-DISEASE, MAPT REGION, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Science & Technology, Molecular epidemiology, Hereditary cancer and cancer-related syndromes [ONCOL 1], MULTIDISCIPLINARY SCIENCES, MICRORNA EXPRESSION, Pair 17, Carcinoma, Human Genome, General Chemistry, Odds ratio, medicine.disease, Human genome, Ovarian cancer
Abstract: Contains fulltext : 118576.pdf (Publisher’s version ) (Open Access) Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Published: 2013

33. Evidence of a genetic link between endometriosis and ovarian cancer

Author: Alice W. Lee, Claire Templeman, Douglas A. Stram, Jonathan Beesley, Jonathan Tyrer, Andrew Berchuck, Paul P. Pharoah, Georgia Chenevix-Trench, Celeste Leigh Pearce, Roberta B. Ness, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Alexander Hein, Alice S. Whittemore, Allan Jensen, Andreas du Bois, Angela Brooks-Wilson, Anja Rudolph, Anna Jakubowska, Anna H. Wu, Argyrios Ziogas, Arif B. Ekici, Arto Leminen, Barry Rosen, Beata Spiewankiewicz, Beth Y. Karlan, Britton Trabert, Brooke L. Fridley, C. Blake Gilks, Camilla Krakstad, Catherine M. Phelan, Cezary Cybulski, Christine Walsh, Claus Hogdall, Daniel W. Cramer, David G. Huntsman, Diana Eccles, Diether Lambrechts, Dong Liang, Douglas A. Levine, Edwin S. Iversen, Elisa V. Bandera, Elizabeth M. Poole, Ellen L. Goode, Els Van Nieuwenhuysen, Estrid Hogdall, Fiona Bruinsma, Florian Heitz, Francesmary Modugno, Graham G. Giles, Harvey A. Risch, Helen Baker, Helga B. Salvesen, Heli Nevanlinna, Hoda Anton-Culver, Honglin Song, Iain McNeish, Ian G. Campbell, Ignace Vergote, Ingo B. Runnebaum, Ingvild L. Tangen, Ira Schwaab, Jacek Gronwald, James Paul, Jan Lubinski, Jennifer A. Doherty, Jenny Chang-Claude, Jenny Lester, Joellen M. Schildkraut, John R. McLaughlin, Jolanta Lissowska, Jolanta Kupryjanczyk, Joseph L. Kelley, Joseph H. Rothstein, Julie M. Cunningham, Karen Lu, Karen Carty, Kathryn L. Terry, Katja K.H. Aben, Kirsten B. Moysich, Kristine G. Wicklund, Kunle Odunsi, Lambertus A. Kiemeney, Lara Sucheston-Campbell, Lene Lundvall, Leon F.A.G. Massuger, Liisa M. Pelttari, Linda E. Kelemen, Linda S. Cook, Line Bjorge, Lotte Nedergaard, Louise A. Brinton, Lynne R. Wilkens, Malcolm C. Pike, Marc T. Goodman, Maria Bisogna, Mary Anne Rossing, Matthias W. Beckmann, Matthias Dürst, Melissa C. Southey, Melissa Kellar, Michelle A.T. Hildebrandt, Nadeem Siddiqui, Natalia Antonenkova, Natalia Bogdanova, Nhu D. Le, Nicolas Wentzensen, Pamela J. Thompson, Patricia Harrington, Penelope M. Webb, Peter A. Fasching, Peter Hillemanns, Philipp Harter, Piotr Sobiczewski, Rachel Palmieri Weber, Ralf Butzow, Robert P. Edwards, Robert A. Vierkant, Rosalind Glasspool, Sandra Orsulic, Sandrina Lambrechts, Sara H. Olson, Shan Wang-Gohrke, Shashi Lele, Shelley S. Tworoger, Simon A. Gayther, Stacey A. Missmer, Steven A. Narod, Susan J. Ramus, Susanne K. Kjaer, Tanja Pejovic, Thilo Dörk, Ursula Eilber, Usha Menon, Valerie McGuire, Weiva Sieh, Xifeng Wu, Yukie Bean, and Yurii B. Shvetsov
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, endocrine system diseases, Endometriosis, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Risk Factors, Internal medicine, Databases, Genetic, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Genetic testing, Ovarian Neoplasms, Gynecology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, Case-control study, Computational Biology, Obstetrics and Gynecology, medicine.disease, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Phenotype, 030104 developmental biology, Reproductive Medicine, Case-Control Studies, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Neoplasm Grading, Ovarian cancer, Genome-Wide Association Study
Abstract: Contains fulltext : 172500.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Published: 2016

34. [Value of fine needle aspiration biopsy in cervical cancer]

Author: Krzysztof, Cendrowski, Włodzimierz, Sawicki, Jerzy, Wygledowski, Beata, Spiewankiewicz, and Jerzy, Stelmachów
Subjects: Aged, 80 and over, Biopsy, Fine-Needle, Uterine Cervical Neoplasms, Middle Aged, Sensitivity and Specificity, Predictive Value of Tests, Vagina, Carcinoma, Squamous Cell, Humans, Female, Neoplasm Invasiveness, Poland, Aged, Ultrasonography
Abstract: Correct staging qualification, especially evaluation of parametrium is very useful in choosing of adequate method of treatment, and thereby in patients' survival.The aim of study was estimation of the value of fine needle aspiration biopsy in transvaginal ultrasonography assistant in preoperative assessment of parametria in cervical cancer. We compared parametrial infiltration before treatment and to verified and confirmed staging in cervical cancer postoperatively by histopathology.64 women with cervical cancer in stage Ib, were included in the study. Assessment of parametrial invasion before treatment was performed by fine needle aspiration biopsy in endovaginal ultrasound assistants. The sonographic evaluation of parametria was performed by Siemens Sonoline Versa Pro with transvaginal 7 MHz mechanical transducer with the biopsy guide 14 cm long. All of patients with cervical cancer in stage Ib were operated on Wertheim-Meigs hysterectomy. The preoperative findings were compared with data obtained by histopathology findings. There were evaluated sensitivity, specificity and diagnostic accuracy of this method.Accuracy of fine needle aspiration biopsy of parametrial involvement was 89%, sensitivity-70%, specificity-92.6%, PPV-63.6%, NPV-94.3%.Transvaginal ultrasonography is superior to routine clinical examination in the assessment of parametria. Sensitivity of fine needle biopsy with ultrasound assistance is higher then of gynecological examination and ultrasound alone. Correct preoperative diagnosis may improve staging, treatment and indirectly, survival patients with cervical cancer.
Published: 2003

35. [Comparison of cerclage and cerclage pessary in the treatment of pregnant women with incompetent cervix and threatened preterm delivery]

Author: Agnieszka, Antczak-Judycka, Włodzimierz, Sawicki, Beata, Spiewankiewicz, Krzysztof, Cendrowski, and Jerzy, Stelmachów
Subjects: Adult, Time Factors, Pregnancy, High-Risk, Infant, Newborn, Pregnancy Outcome, Cervix Uteri, Middle Aged, Pessaries, Obstetric Labor, Premature, Treatment Outcome, Pregnancy, Risk Factors, Humans, Female, Uterine Cervical Incompetence, Cerclage, Cervical
Abstract: Cervical incompetence is one of the causes of preterm delivery. Ultrasound examination of the cervix has given the evidence that cervical shortening, dilatation of internal cervical os and funneling observed long before term are the warning signs of preterm delivery. Early diagnosis and treatment may serve better outcome. Cerclage, which has been employed for more than 50 years is a traumatic procedure, furthermore requiring anaesthesia. Cerclage pessary can be a safe alternative to cerclage. This method seems to be less invasive. The aim of the study was to compare the effectiveness of the two methods employed in gravid patients between 22 and 27 completed weeks of pregnancy with clinically and ultrasonographically confirmed shortening of the cervix.We analysed 57 patients, 22 treated with McDonald cerclage procedure and 35 with pessary. The primary outcome measure was prolongation of pregnancy--mean 13.4 weeks and 12.1 weeks for cerclage and pessary respectively (p = 0.06). There were no significant differences regarding the mode of delivery, rate of prematurity, mean birthweight and Apgar score.Cerclage and cerclage pessary are equally effective methods of prolongation of pregnancy in gravid patients with incompetent cervix and threatened preterm labor. The choice of the method does not affect the mode of delivery as well as neonatal outcome.
Published: 2003

36. P223 Endometrial effects during long-term hormonal replacement therapy

Author: Jerzy Stelmachów and Beata Spiewankiewicz
Subjects: Oncology, medicine.medical_specialty, business.industry, Internal medicine, Hormonal replacement therapy, medicine, Obstetrics and Gynecology, business, General Biochemistry, Genetics and Molecular Biology, Term (time)
Published: 1996

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