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

Author

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

Abstract

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Published
2023

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

Author

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

Abstract

Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network

Published
2023

6. Supplementary References from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Author

Lin Zhang, George Coukos, Carlo M. Croce, Ralf Bützow, Barbara L. Weber, George Adrian Calin, Dionyssios Katsaros, Qihong Huang, Chang-Gong Liu, Xian-Ming Chen, Cameron N. Johnstone, Lori Smith, Shan Deng, Arto Leminen, Shun Liang, Kosei Hasegawa, Heini Lassus, Joel Greshock, Stefano Volinia, Sippy Kaur, and Nuo Yang

Abstract

Supplementary References from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Published
2023

12. Supplementary Figure 1 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Author

Lin Zhang, George Coukos, Carlo M. Croce, Ralf Bützow, Barbara L. Weber, George Adrian Calin, Dionyssios Katsaros, Qihong Huang, Chang-Gong Liu, Xian-Ming Chen, Cameron N. Johnstone, Lori Smith, Shan Deng, Arto Leminen, Shun Liang, Kosei Hasegawa, Heini Lassus, Joel Greshock, Stefano Volinia, Sippy Kaur, and Nuo Yang

Abstract

Supplementary Figure 1 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Published
2023

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

Author

Ellen L. Goode, Brooke L. Fridley, Julie M. Cunningham, Keith L. Knutson, Kirsten Moysich, Paul D.P. Pharoah, Linda E. Kelemen, Piotr Sobiczewski, Michelle A.T. Hildebrandt, Montserrat Garcia-Closas, Ignace Vergote, Joseph H. Rothstein, Grace Friel, Francesmary Modugno, Arto Leminen, Lynne R. Wilkens, Arif B. Ekici, Janusz Menkiszak, Urmila Chandran, Ira Schwaab, Aleksandra Gentry-Maharaj, Mari K. Halle, David van den Berg, Anne M. Van Altena, Liisa M. Pelttari, Matthias W. Beckmann, Hannah Yang, Sandrina Lambrechts, Lukasz M. Szafron, Shan Wang-Gohrke, Lene Lundvall, Andreas du Bois, Jenny Lester, Valerie McGuire, Robert Edwards, Lara Sucheston, Jie Lin, Cezary Cybulski, Elisabeth Wik, Susan J. Ramus, Malcolm C. Pike, Katja K. Aben, Angela Brooks-Wilson, Allison F. Vitonis, Jonathan Tyrer, Philipp Harter, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Anja Rudolph, Alexander Hein, Louise Brinton, Evelyn Despierre, Christine Walsh, Argyrios Ziogas, Galina Lurie, Yukie T. Bean, Heli Nevanlinna, Jan Lubiński, Allan Jensen, Andrew Berchuck, Kunle Odunsi, Dong Liang, Camilla Krakstad, Jennifer A. Doherty, Honglin Song, Leon F.A.G. Massuger, Robert Brown, Catherine M. Phelan, James M. Flanagan, Daniel Cramer, Susanne Kruger Kjaer, Douglas A. Levine, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Peter A. Fasching, Diether Lambrechts, Claus K. Hogdall, Jacek Gronwald, Hoda Anton-Culver, Beth Y. Karlan, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Simon A. Gayther, Anna H. Wu, James Paul, Diana Eccles, Ingo B. Runnebaum, Natalia Bogdanova, Clareann H. Bunker, Nhu D. Le, Ian Campbell, Tanja Pejovic, Thilo Dörk, Ralf Butzow, Karen Lu, Jolanta Kupryjanczyk, Steven A. Narod, Roberta B. Ness, Mary Anne Rossing, Linda S. Cook, Pamela J. Thompson, Marc T. Goodman, Kathryn Terry, Irene Orlow, Elisa V. Bandera, Jenny Chang-Claude, Weiva Sieh, Alice S. Whittemore, Georgia Chenevix-Trench, Nicolas Wentzensen, Britton Trabert, Gianluca Severi, Graham G. Giles, Laura Baglietto, Lambertus A. Kiemeney, Helga B. Salvesen, Harvey A. Risch, Elizabeth Poole, Shelley S. Tworoger, Thomas A. Sellers, David N. Rider, Zachary Fogarty, Kimberly R. Kalli, Robert A. Vierkant, William R. Bamlet, Matthew S. Block, and Bridget Charbonneau

Abstract

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Published
2023

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

Author

Ellen L. Goode, Brooke L. Fridley, Julie M. Cunningham, Keith L. Knutson, Kirsten Moysich, Paul D.P. Pharoah, Linda E. Kelemen, Piotr Sobiczewski, Michelle A.T. Hildebrandt, Montserrat Garcia-Closas, Ignace Vergote, Joseph H. Rothstein, Grace Friel, Francesmary Modugno, Arto Leminen, Lynne R. Wilkens, Arif B. Ekici, Janusz Menkiszak, Urmila Chandran, Ira Schwaab, Aleksandra Gentry-Maharaj, Mari K. Halle, David van den Berg, Anne M. Van Altena, Liisa M. Pelttari, Matthias W. Beckmann, Hannah Yang, Sandrina Lambrechts, Lukasz M. Szafron, Shan Wang-Gohrke, Lene Lundvall, Andreas du Bois, Jenny Lester, Valerie McGuire, Robert Edwards, Lara Sucheston, Jie Lin, Cezary Cybulski, Elisabeth Wik, Susan J. Ramus, Malcolm C. Pike, Katja K. Aben, Angela Brooks-Wilson, Allison F. Vitonis, Jonathan Tyrer, Philipp Harter, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Anja Rudolph, Alexander Hein, Louise Brinton, Evelyn Despierre, Christine Walsh, Argyrios Ziogas, Galina Lurie, Yukie T. Bean, Heli Nevanlinna, Jan Lubiński, Allan Jensen, Andrew Berchuck, Kunle Odunsi, Dong Liang, Camilla Krakstad, Jennifer A. Doherty, Honglin Song, Leon F.A.G. Massuger, Robert Brown, Catherine M. Phelan, James M. Flanagan, Daniel Cramer, Susanne Kruger Kjaer, Douglas A. Levine, Celeste Leigh Pearce, Joellen Schildkraut, Usha Menon, Peter A. Fasching, Diether Lambrechts, Claus K. Hogdall, Jacek Gronwald, Hoda Anton-Culver, Beth Y. Karlan, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Simon A. Gayther, Anna H. Wu, James Paul, Diana Eccles, Ingo B. Runnebaum, Natalia Bogdanova, Clareann H. Bunker, Nhu D. Le, Ian Campbell, Tanja Pejovic, Thilo Dörk, Ralf Butzow, Karen Lu, Jolanta Kupryjanczyk, Steven A. Narod, Roberta B. Ness, Mary Anne Rossing, Linda S. Cook, Pamela J. Thompson, Marc T. Goodman, Kathryn Terry, Irene Orlow, Elisa V. Bandera, Jenny Chang-Claude, Weiva Sieh, Alice S. Whittemore, Georgia Chenevix-Trench, Nicolas Wentzensen, Britton Trabert, Gianluca Severi, Graham G. Giles, Laura Baglietto, Lambertus A. Kiemeney, Helga B. Salvesen, Harvey A. Risch, Elizabeth Poole, Shelley S. Tworoger, Thomas A. Sellers, David N. Rider, Zachary Fogarty, Kimberly R. Kalli, Robert A. Vierkant, William R. Bamlet, Matthew S. Block, and Bridget Charbonneau

Abstract

PDF file - 145K, Supplementary Table 1. Studies in the Ovarian Cancer Association Consortium (OCAC) are listed, as well as the abbreviation, location, type, and number of cases and controls for each study. Supplementary Table 2. The number of cases included in the analysis from each OCAC study site is listed by histologic subtype. Supplementary Table 3. Gene symbols and IDs are listed for NF-κB pathway genes that were tagged in this study, as well as chromosome position, number of SNPs tagged, and bin coverage of each gene using Hapmap or 1000 genomes as a reference. Supplementary Table 4. Reasons and numbers of samples excluded from the analysis following the sample quality control are described. Supplementary Table 5. We evaluated rs17561 and rs6785617 for interactions with known epidemiologic risk factors for risk of clear cell and LMP tumors, respectively, and report interaction p-values in the table below.

Published
2023

15. Supplementary Table 2 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Author

Lin Zhang, George Coukos, Carlo M. Croce, Ralf Bützow, Barbara L. Weber, George Adrian Calin, Dionyssios Katsaros, Qihong Huang, Chang-Gong Liu, Xian-Ming Chen, Cameron N. Johnstone, Lori Smith, Shan Deng, Arto Leminen, Shun Liang, Kosei Hasegawa, Heini Lassus, Joel Greshock, Stefano Volinia, Sippy Kaur, and Nuo Yang

Abstract

Supplementary Table 2 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Published
2023

17. Supplementary Table 1 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Author

Lin Zhang, George Coukos, Carlo M. Croce, Ralf Bützow, Barbara L. Weber, George Adrian Calin, Dionyssios Katsaros, Qihong Huang, Chang-Gong Liu, Xian-Ming Chen, Cameron N. Johnstone, Lori Smith, Shan Deng, Arto Leminen, Shun Liang, Kosei Hasegawa, Heini Lassus, Joel Greshock, Stefano Volinia, Sippy Kaur, and Nuo Yang

Abstract

Supplementary Table 1 from MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

Published
2023

20. Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Author

Bhagwan Yadav, Arto Leminen, Matti Kankainen, Anniina Färkkilä, Noora Andersson, Annika Riska, Jing Tang, Evgeny Kulesskiy, Leila Unkila-Kallio, Ulla-Maija Haltia, Olli Kallioniemi, Ralf Bützow, Mikko Anttonen, Krister Wennerberg, Markku Heikinheimo, Tero Aittokallio, Department of Obstetrics and Gynecology, University of Helsinki, Clinicum, Children's Hospital, Precision Cancer Pathology, Institute for Molecular Medicine Finland, HUSLAB, Department of Pathology, Medicum, Developmental and tumor biology research group, Olli-Pekka Kallioniemi / Principal Investigator, Krister Wennerberg / Principal Investigator, Tero Aittokallio / Principal Investigator, Bioinformatics, Department of Clinical Chemistry and Hematology, HUS Gynecology and Obstetrics, HUS Children and Adolescents, and Precision Systems Medicine

Subjects
0301 basic medicine, Dasatinib, Pharmacology, chemistry.chemical_compound, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Antineoplastic Combined Chemotherapy Protocols, Granulosa Cell Tumor, Aged, 80 and over, Ovarian Neoplasms, TOR Serine-Threonine Kinases, Obstetrics and Gynecology, BREAST-CANCER CELLS, Drug Synergism, CHEMOTHERAPY, BLEOMYCIN, Middle Aged, SOLID TUMORS, 3. Good health, Oncology, Paclitaxel, 030220 oncology & carcinogenesis, Female, medicine.drug, EXPRESSION, Granulosa cell, 3122 Cancers, Bleomycin, 03 medical and health sciences, Ovarian cancer, Cell Line, Tumor, medicine, Humans, MYELOID-LEUKEMIA, COMBINATION, PI3K/AKT/mTOR pathway, TERM-FOLLOW-UP, Aged, Everolimus, business.industry, ta3121, medicine.disease, ta3122, ta3123, 030104 developmental biology, MRNA Sequencing, chemistry, MAMMALIAN TARGET, Kinase inhibitors, Screening strategies, Cancer research, ESTABLISHMENT, Drug Screening Assays, Antitumor, business
Abstract

Objective. Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. Methods. The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. Results. Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. Conclusions. We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options. (C) 2016 Elsevier Inc. All rights reserved.

Published
2017

21. Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors

Author

Annika Riska, Saara Bryk, Ralf Bützow, Markku Heikinheimo, Anniina Färkkilä, Leila Unkila-Kallio, Johanna Tapper, Arto Leminen, Developmental and tumor biology research group, Clinicum, HUS Children and Adolescents, HUS Gynecology and Obstetrics, HUSLAB, Department of Pathology, and Department of Obstetrics and Gynecology

Subjects
Forkhead Box Protein L2, Oncology, Ovarian Granulosa Cell, Granulosa cell tumor, Kaplan-Meier Estimate, Cohort Studies, Gynecologic Surgical Procedures, PROGNOSTIC-FACTORS, 0302 clinical medicine, Risk Factors, Recurrence, 3123 Gynaecology and paediatrics, Stage (cooking), Finland, Aged, 80 and over, 030219 obstetrics & reproductive medicine, Age Factors, Obstetrics and Gynecology, Forkhead Transcription Factors, Middle Aged, Prognosis, University hospital, Tumor Burden, 3. Good health, Predictive factor, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Cohort, SURVIVAL, Female, Adult type, medicine.symptom, Adult, medicine.medical_specialty, 3122 Cancers, Asymptomatic, Disease-Free Survival, 03 medical and health sciences, Internal medicine, medicine, Humans, Initial treatment, TERM-FOLLOW-UP, Aged, Neoplasm Staging, Proportional Hazards Models, Retrospective Studies, Rupture, Rupture, Spontaneous, business.industry, Surgery, Premenopause, Multivariate Analysis, Lymph Node Excision, Neoplasm Recurrence, Local, business
Abstract

Objective. Adult-type ovarian granulosa cell tumors (AGCTs) have an unpredictable tendency to relapse. In a carefully validated patient cohort, we evaluated the prognostic factors related to AGCT recurrence. Methods. We identified all patients diagnosed with AGCT during 1956-2014 in Helsinki University Hospital, with a minimum follow-up of one year (n = 240). After a histological review supplemented with FOXL2 (402C G) mutation status analysis, we analyzed the clinical data for association with relapse. Results. The final cohort included 164 (68%) molecularly defined AGCTs (MD-AGCTs). The majority of the women were postmenopausal (63%), and 92% of tumors were stage I. The median follow-up time was 15.5 years. Fifty-two (32%) patients developed tumor recurrence, of whom 55% had successive recurrences. Multiple-site recurrences were common, and nearly half of the recurrences were asymptomatic. The median time to the first relapse was 7.4 years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3 years. Premenopausal status at initial diagnosis, FIGO stage Ic versus la, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGO' in a median time of 153 years. Conclusion. Tumor rupture is the strongest predictive factor for recurrence, and these patients might benefit from a more aggressive initial treatment approach. AGCT requires active follow up for 10 to 15 years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations. (C) 2016 Elsevier Inc. All rights reserved.

Published
2016

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

Author

John McLaughlin, Hanna Yang, Francesmary Modugno, Jennifer B. Permuth, Diana Eccles, Agnieszka Dansonka-Mieszkowska, Matthias W. Beckmann, Elizabeth M. Poole, Pamela J. Thompson, Maria Bisogna, Ellen L. Goode, Michelle A.T. Hildebrandt, Paul D.P. Pharoah, Zhihua Chen, Lambertus A. Kiemeney, Madalene Earp, Claus Høgdall, Jin Q. Cheng, Xifeng Wu, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Stacey J. Winham, Jan Lubinski, Andrew Berchuck, Valerie McGuire, Els Van Niewenhuyse, Arto Leminen, Ralf Bützow, Susan J. Ramus, Angela Brooks-Wilson, Joseph H. Rothstein, Argyrios Ziogas, Ignace Vergote, Ian G. Campbell, Steven A. Narod, Daniel W. Cramer, Simon A. Gayther, Diether Lambrechts, Heli Nevanlinna, Harvey A. Risch, Alice S. Whittemore, Lene Lundvall, Jolanta Lissowska, Kunle Odunsi, Kathryn L. Terry, Y. Ann Chen, Jacek Gronwald, Leon F.A.G. Massuger, Alvaro N.A. Monteiro, Louise A. Brinton, Marc T. Goodman, Celeste Leigh Pearce, Roberta B. Ness, Peter A. Fasching, Joseph L. Kelley, Linda E. Kelemen, Yurii B. Shvetsov, Elisa V. Bandera, Susanne K. Kjaer, Joellen M. Schildkraut, Graham G. Giles, Georgia Chenevix-Trench, Irene Orlow, Weiva Sieh, Liisa M. Pelttari, Catherine M. Phelan, Melissa Moffitt, Brett M. Reid, Jenny Lester, Adriaan Vanderstichele, Linda S. Cook, Usha Menon, Dong Liang, Brooke L. Fridley, Mary Anne Rossing, Julie M. Cunningham, Thilo Dörk, Douglas A. Levine, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Hoda Anton-Culver, Nhu D. Le, Honglin Song, Anna H. Wu, Kirsten B. Moysich, Line Bjørge, Sara H. Olson, Lynne R. Wilkens, Iain A. McNeish, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Natalia Bogdanova, Jennifer A. Doherty, Robert P. Edwards, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, and Estrid Høgdall

Subjects
0301 basic medicine, RNA editing, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, ovarian cancer risk, Gene expression, Animals, Humans, Gene, Genetic association, Ovarian Neoplasms, Genetics, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Genetic Variation, Middle Aged, 3. Good health, 030104 developmental biology, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Expression quantitative trait loci, ADAR, Female, Disease Susceptibility, polymorphisms, Priority Research Paper
Abstract

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P

Published
2016

23. 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

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

Author

Jolanta Lissowska, Janusz Menkiszak, Louise A. Brinton, Tomasz Huzarski, Sara H. Olson, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Marc T. Goodman, Kenneth D. Swenerton, Susanne K. Kjaer, Rosalind Glasspool, Joseph L. Kelley, Bobbie J. Rimel, Estrid Høgdall, Yurii B. Shvetsov, Argyrios Ziogas, Joellen M. Schildkraut, Jennifer A. Doherty, Weiva Sieh, Christina M. Nagle, Kirsten B. Moysich, Xifeng Wu, Angela Brooks-Wilson, Agnieszka Budzilowska, Roberta B. Ness, James Paul, Jonathan Tyrer, Agnieszka Dansonka-Mieszkowska, Diana Eccles, Philipp Harter, Francesmary Modugno, Melissa C. Southey, Tjoung Won Park-Simon, Penelope M. Webb, Hannah P. Yang, Graham G. Giles, Matthias W. Beckmann, Sandrina Lambrechts, Anna H. Wu, Paul D.P. Pharoah, Lambertus A. Kiemeney, Suzanne C. Dixon-Suen, Valerie McGuire, Maria Bisogna, Ian G. Campbell, Linda E. Kelemen, Andreas du Bois, Aleksandra Gentry-Maharaj, Nhu D. Le, Jenny Chang-Claude, Ellen L. Goode, Els Van Nieuwenhuysen, Robert P. Edwards, Simon A. Gayther, Harvey A. Risch, Line Bjørge, Ignace Vergote, Michelle A.T. Hildebrandt, Ira Schwaab, Arto Leminen, Nadeem Siddiqui, Aaron P. Thrift, Susan J. Ramus, Elisa V. Bandera, Stacey J. Winham, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Brooke L. Fridley, Tanja Pejovic, Florian Heitz, Jolanta Kupryjanczyk, Beth Y. Karlan, Nicolas Wentzensen, Karen H. Lu, Malcolm C. Pike, Claus Høgdall, Linda S. Cook, John R. McLaughlin, Georgia Chenevix-Trench, Peter Hillemanns, Roger L. Milne, Catherine M. Phelan, Sandra Orsulic, Reidun K. Kopperud, Jenny Lester, Alice S. Whittemore, Diether Lambrechts, Kunle Odunsi, Jacek Gronwald, Kathryn L. Terry, Hoda Anton-Culver, Chiu-Chen Tseng, Amanda S. Bruegl, Andrew Berchuck, Lene Lundvall, Ailith Ewing, Ralf Bützow, Peter A. Fasching, Honglin Song, Pamela J. Thompson, Julie M. Cunningham, Joseph H. Rothstein, Allan Jensen, Wei Zheng, Leon F.A.G. Massuger, Audrey Y. Jung, Fiona Bruinsma, Iwona K. Rzepecka, Steven A. Narod, Daniel W. Cramer, Liisa M. Pelttari, Liv Cecilie Vestrheim Thomsen, Usha Menon, Dong Liang, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, and Heli Nevanlinna

Subjects
0301 basic medicine, Oncology, Adult, Cancer Research, medicine.medical_specialty, Adolescent, Carcinoma, Ovarian Epithelial, Carcinoma, Ovarian Epithelial/epidemiology, Article, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Risk Factors, Internal medicine, Epidemiology of cancer, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Aged, Ovarian Neoplasms, Aged, 80 and over, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Body Height/genetics, Geography, Confounding, Case-control study, Odds ratio, Mendelian Randomization Analysis, Middle Aged, medicine.disease, Body Height, Confidence interval, 3. Good health, 030104 developmental biology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Meta-analysis, Case-Control Studies, Female, Ovarian Neoplasms/epidemiology, Ovarian cancer, Body mass index
Abstract

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

Published
2018

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

Author

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

Subjects
endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Published
2015

26. 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

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

Author

Jenny Lester, Arif B. Ekici, Xiao-Ou Shu, Georgia Chenevix-Trench, Julie M. Cunningham, Catherine M. Phelan, Tassja J. Spindler, Shelley S. Tworoger, Allan Jensen, Diana Eccles, Wei Zheng, Satoyo Hosono, Svend Aage Engelholm, Linda S. Cook, Thomas A. Sellers, John R. McLaughlin, Matthias W. Beckmann, Elizabeth M. Poole, Ignace Vergote, Francesmary Modugno, Jennifer A. Doherty, Sandrina Lambrechts, Lara Sucheston, Wang Gohrke Shan, Rosalind Glasspool, Barry P. Rosen, Pamela J. Thompson, Christine Walsh, Camilla Krakstad, Jennifer Permuth-Wey, Hoda Anton-Culver, Ralf Bützow, Ed Dicks, Yin Ling Woo, Honglin Song, Qiyuan Li, Leon F.A.G. Massuger, Yurii B. Shvetsov, Joellen M. Schildkraut, Xiaoqing Chen, Hannah P. Yang, Graham G. Giles, Sara H. Olson, Edwin S. Iversen, Claus Høgdall, Jacek Grownwald, Fiona Bruinsma, Peter Hillemanns, Iwona K. Rzepecka, Douglas T. Easton, Robert P. Edwards, Lynne R. Wilkens, Yukie Bean, Y. Ann Chen, Jonathan Tyrer, Tanja Pejovic, Patricia Harrington, Iain A. McNeish, Steven A. Narod, Joanna Moes-Sosnowska, Hanis Nazihah Hasmad, Ji-Heui Seo, Line Bjørge, Peter A. Fasching, Daniel W. Cramer, Florian Heitz, Beth Y. Karlan, Cezary Cybulski, Simon A. Gayther, Jolanta Kupryjanczyk, Nhu D. Le, Alexander Hein, Soo Hwang Teo, Nicolas Wentzensen, Valerie McGuire, Michelle A.T. Hildebrandt, Argyrios Ziogas, Heli Nevanlinna, Karen H. Lu, Diether Lambrechts, Kirsten B. Moysich, Jonathan Beesley, Kate Lawrenson, Ian G. Campbell, Andrew Berchuck, Philipp Harter, Lene Lundvall, Sandra Orsulic, Kathryn L. Terry, Jolanta Lissowska, Helen Baker, Matthew L. Freedman, Linda E. Kelemen, Maria Bisogna, Celeste Leigh Pearce, Ira Schwaab, Elisa V. Bandera, Kristine G. Wicklund, Arto Leminen, Nadeem Siddiqui, Joseph H. Rothstein, Melissa Kellar, Matthias Dürst, Harvey A. Risch, Włodzimierz Sawicki, Katja K.H. Aben, Alice S. Whittemore, Kunle Odunsi, Shashi Lele, Noor Azmi Mat Adenan, Susanne K. Kjaer, Robert A. Vierkant, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Anja Rudolph, Els Van Nieuwenhuysen, Irene Orlow, Joe Dennis, Ingvild L. Tangen, Estrid Høgdall, Alice W. Lee, Roberta B. Ness, James Paul, Malcolm C. Pike, Rachel Palmieri Weber, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Natalia Antonenkova, Anne M. van Altena, Xifeng Wu, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Weiva Sieh, Lambertus A. Kiemeney, Lotte Nedergaard, Ursula Eilber, Janet M. Lee, Zhihua Chen, Andreas du Bois, Joseph L. Kelley, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Bu Tian Ji, Liisa M. Pelttari, Usha Menon, Dong Liang, Yu-Tang Gao, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Louise A. Brinton, Marc T. Goodman, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, and Susan J. Ramus

Subjects
Green Fluorescent Proteins, Molecular Sequence Data, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cell Line, Tumor, Ovarian carcinoma, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genetic association, Cell Nucleus, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, medicine.disease, Adenocarcinoma, Mucinous, Neoplasm Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Gene Expression Regulation, Neoplastic, Microscopy, Fluorescence, Chromosomes, Human, Pair 2, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Adenocarcinoma, Female, Ovarian cancer, Genome-Wide Association Study
Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Published
2015

28. The clinical utility of serum anti-Müllerian hormone in the follow-up of ovarian adult-type granulosa cell tumors-A comparative study with inhibin B

Author

Juha S. Tapanainen, Ulla Puistola, Ralf Bützow, Anniina Färkkilä, Leila Unkila-Kallio, Sanna Koskela, Saara Bryk, Henrik Alfthan, Mikko Anttonen, Markku Heikinheimo, and Arto Leminen

Subjects
endocrine system, Cancer Research, medicine.medical_specialty, endocrine system diseases, biology, business.industry, Area under the curve, Anti-Müllerian hormone, medicine.disease, female genital diseases and pregnancy complications, Confidence interval, Endocrinology, Oncology, Internal medicine, medicine, biology.protein, Young adult, Ovarian cancer, Prospective cohort study, business, hormones, hormone substitutes, and hormone antagonists, Cohort study, Hormone
Abstract

Ovarian adult-type granulosa cell tumors (AGCTs) require prolonged follow-up, but evidence regarding the optimal follow-up marker is lacking. The objective of our study was to validate the clinical usefulness of serum anti-Mullerian hormone (AMH) and the current marker inhibin B as single and combined markers of AGCTs. We conducted a longitudinal, partially prospective cohort study of 123 premenopausal and postmenopausal AGCT patients with a median follow-up time of 10.5 years (range 0.3-50.0 years). Serum AMH and inhibin B levels were measured from 560 pretreatment and follow-up serum samples by using immunoenzymometric assays. We found that serum AMH and inhibin B levels were significantly elevated in patients with primary or recurrent AGCTs. The levels of both markers positively correlated to tumor size (p

Published
2015

29. Prediction of Site-Specific Tumor Relapses in Patients With Stage I-II Endometrioid Endometrial Cancer

Author

Ralf Bützow, Taru Tuomi, Mikko Loukovaara, Annukka Pasanen, and Arto Leminen

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Stromal Invasion, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, Carcinoma, medicine, Adjuvant therapy, Humans, Neoplasm Invasiveness, Stage (cooking), Aged, Neoplasm Staging, 2. Zero hunger, Univariate analysis, 030219 obstetrics & reproductive medicine, business.industry, Endometrial cancer, Obstetrics and Gynecology, Cell Differentiation, Odds ratio, medicine.disease, 3. Good health, Endometrial Neoplasms, Radiation therapy, 030220 oncology & carcinogenesis, Female, business, Carcinoma, Endometrioid
Abstract

Objective The aim of this study was to investigate the association of predictors of an advanced disease and/or poor outcome with the occurrence of tumor relapses in different anatomical sites in patients with stage I–II endometrioid endometrial cancer. Methods A total of 929 patients were included in the study. The median follow-up time was 57 months (range, 1–108 months). The studied variables were: poor tumor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, lymphovascular space invasion, cervical stromal invasion, positive peritoneal cytology, old age (>77 years), obesity (body mass index ≥30 kg/m2), and diabetes. Results A relapse was diagnosed in 98 patients (10.5%) (vaginal in 15, pelvic in 27, intra-abdominal beyond the pelvis in 27, extra-abdominal in 29). None of the variables were associated with an altered risk of vaginal or pelvic relapses in univariate analyses. Poor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, and positive peritoneal cytology were associated with an increased risk of intra-abdominal relapses beyond the pelvis (odds ratios [ORs] between 2.2 and 9.6). With the exception of obesity and diabetes, all variables were associated with an increased risk of extra-abdominal relapses (ORs between 2.3 and 13). Tumor size 3 cm or greater (OR, 3.1) and positive peritoneal cytology (OR, 16) predicted intra-abdominal relapses beyond the pelvis in multivariate analysis, whereas poor differentiation (OR, 2.9), myometrial invasion 50% or greater (OR, 4.0), and positive peritoneal cytology (OR, 27) predicted extra-abdominal relapses. Compared with vaginal relapses, intra-abdominal relapses beyond the pelvis and extra-abdominal relapses were associated with a worse disease-specific survival. Survival of patients with a pelvic relapse did not differ from that of patients with a vaginal relapse. Conclusions Risk variables of endometrial cancer are differently associated with relapses in different locations. Our findings may promote studies that explore the most efficient adjuvant therapy in high-risk early-stage endometrioid endometrial cancer.

Published
2017

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

Author

Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract

The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

Published
2017

31. Prediction of Para-aortic Spread by Gross Pelvic Lymph Node Findings in Patients With Endometrial Carcinoma

Author

Mikko Loukovaara, Anna Luomaranta, Ralf Bützow, Jouko Lohi, and Arto Leminen

Subjects
medicine.medical_specialty, medicine.medical_treatment, Metastasis, Predictive Value of Tests, medicine, Carcinoma, Humans, Stage (cooking), Lymph node, Neoplasm Staging, Pelvic Neoplasms, Gynecology, business.industry, Obstetrics and Gynecology, Cancer, Middle Aged, medicine.disease, Endometrial Neoplasms, medicine.anatomical_structure, Oncology, Lymph Node Excision, Adenocarcinoma, Female, Lymphadenectomy, Lymph Nodes, Lymph, Radiology, business, Follow-Up Studies
Abstract

ObjectiveIsolated para-aortic lymph node metastases are rare in patients with endometrial carcinoma. We wanted to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in these patients.MethodsWe identified all women with surgically treated endometrial carcinoma at our institution between January 2008 and February 2013 (n = 854). One hundred seventeen patients received pelvic-aortic lymphadenectomy. Lymph nodes were considered grossly positive based on size and morphology.ResultsIn patients who underwent comprehensive lymphadenectomy, grossly positive pelvic nodes predicted para-aortic metastasis with a sensitivity of 52.4% and specificity of 93.8%. The positive and negative likelihood ratios were 8.4 and 0.51, respectively. The predictive power of grossly positive pelvic nodes remained significant (odds ratio, 18; 95% confidence interval, 4.1–78; P < 0.0001) after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. The whole sample of 854 patients was used for Bayesian calculations. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. The negative predictive value of the test (ie, grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis) was 99.7% for patients with superficial grade 1 to 2 endometrioid carcinomas and 98.0% for patients with deeply invasive grade 1 to 2 endometrioid carcinomas. For patients with grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive values were 97.3% and 92.2%, respectively. For the whole study population, the value was 98.4%.ConclusionsWhen uterine factors are used for risk stratification of endometrial carcinomas, selective para-aortic lymphadenectomy, based on gross findings of pelvic nodes, is feasible for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. Similarly, gross findings of pelvic nodes can be used to evaluate the need for para-aortic lymphadenectomy in the strategy of routine pelvic lymphadenectomy.

Published
2014

32. HER2 and GATA4 are new prognostic factors for early-stage ovarian granulosa cell tumor—a long-term follow-up study

Author

Noora Andersson, Ralf Bützow, Anniina Färkkilä, Mikko Anttonen, Arto Leminen, Markku Heikinheimo, Leila Unkila-Kallio, Clinicum, Children's Hospital, Department of Obstetrics and Gynecology, Department of Pathology, Haartman Institute (-2014), Developmental and tumor biology research group, HUS Gynecology and Obstetrics, and HUS Children and Adolescents

Subjects
Oncology, Adult, Cancer Research, medicine.medical_specialty, Multivariate analysis, recurrence, Microarray, Receptor, ErbB-2, education, 3122 Cancers, In situ hybridization, Biology, survival, Disease-Free Survival, 03 medical and health sciences, GATA4, 0302 clinical medicine, granulosa cell tumor, 3123 Gynaecology and paediatrics, Internal medicine, HER2, medicine, Humans, Radiology, Nuclear Medicine and imaging, Nuclear atypia, Stage (cooking), prognostic factor, 030304 developmental biology, Original Research, Aged, Aged, 80 and over, 0303 health sciences, Hazard ratio, Middle Aged, Prognosis, 3. Good health, GATA4 Transcription Factor, Gene Expression Regulation, Neoplastic, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Cancer research, Female, Neoplasm Recurrence, Local, Follow-Up Studies
Abstract

Granulosa cell tumors (GCTs) carry a risk of recurrence also at an early stage, but reliable prognostic factors are lacking. We assessed clinicopathological prognostic factors and the prognostic roles of the human epidermal growth factor receptors (HER 2-4) and the transcription factor GATA4 in GCTs. We conducted a long-term follow-up study of 80 GCT patients with a mean follow-up time of 16.8 years. A tumor-tissue microarray was immunohistochemically stained for HER2-4 and GATA4. Expression of HER2-4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization. The results were correlated to clinical data on recurrences and survival. We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%. Tumor recurrence was detected in 24% of the patients at a median of 7.0 years (range 2.6-18 years) after diagnosis. Tumor stage was not prognostic of disease-free survival (DFS). Of the molecular prognostic factors, high-level expression of HER2, and GATA4, and high nuclear atypia were prognostic of shorter DFS. In multivariate analyses, high-level coexpression of HER2 and GATA4 independently predicted DFS (hazard ratio [HR] 8.75, 95% CI 2.20-39.48, P = 0.002). High-level expression of GATA4 also predicted shorter DSS (HR 3.96, 95% CI 1.45-12.57, P = 0.006). In multivariate analyses, however, tumor stage (II-III) and nuclear atypia were independent prognostic factors of DSS. In conclusion HER2 and GATA4 are new molecular prognostic markers of GCT recurrence, which could be utilized to optimize the management and follow-up of patients with early-stage GCTs.

Published
2014

33. Health-related quality of life and perception of anxiety in women with abnormal cervical cytology referred for colposcopy: an observational study

Author

Harri Sintonen, Arto Leminen, Anna-Maija Tapper, Annu Heinonen, and Risto O. Roine

Subjects
Adult, medicine.medical_specialty, Adolescent, Population, Anxiety, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, education, Aged, Retrospective Studies, Colposcopy, education.field_of_study, medicine.diagnostic_test, business.industry, Obstetrics and Gynecology, Middle Aged, Uterine Cervical Dysplasia, medicine.disease, humanities, 3. Good health, Distress, Reproductive Medicine, Dysplasia, 030220 oncology & carcinogenesis, Quality of Life, Physical therapy, Female, Observational study, medicine.symptom, business, Psychosocial
Abstract

Objective To evaluate health-related quality of Life (HRQoL) in patients with abnormal cervical cytology referred for colposcopy. Study design An observational study with prospective and retrospective cohorts. In the prospective arm 240 women referred for colposcopy filled in the 15D HRQoL and the State Anxiety Inventory (STAI) questionnaires and were followed up for 12 months. In the retrospective arm 208 patients who had been treated for cervical dysplasia eight years earlier filled in the 15D HRQoL questionnaire. Results were compared with the age- and sex-standardized general population. Results In the prospective part of the study, the mean 15D score of the patients did not differ from that of the general population. On the dimensions of sleeping, distress and sexual activity, however, the patients scored lower than the general population (p

Published
2013

34. Prediction of lymph node and distant metastasis in patients with endometrial carcinoma: A new model based on demographics, biochemical factors, and tumor histology

Author

Mikko Loukovaara, Arto Leminen, and Anna Luomaranta

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Logistic regression, Body Mass Index, Endometrium, Internal medicine, Carcinoma, medicine, Humans, Stage (cooking), Lymph node, Aged, Demography, Neoplasm Staging, business.industry, Obstetrics and Gynecology, Odds ratio, Middle Aged, Sentinel node, Prognosis, medicine.disease, Endometrial Neoplasms, medicine.anatomical_structure, Area Under Curve, CA-125 Antigen, Lymphatic Metastasis, Lymph Node Excision, Adenocarcinoma, Female, Lymphadenectomy, business
Abstract

Objective To develop a model that might predict the probability of lymph node and distant metastasis (stages IIIC–IV) in endometrial carcinoma. Methods We studied 774 patients with endometrial carcinoma treated in a single institution. Demographic factors, biochemical factors and preoperative tumor characteristics, identified as potential risk factors for advanced carcinoma in unadjusted analyses, were used to create a logistic regression model with lymph node and distant metastasis as the dependent variable. Statistically significant odds ratios in the regression model were rounded to the nearest whole number. These rounded values were the estimated weights for each factor that were summed to generate a score that might predict the probability of stage IIIC–IV carcinoma. Results Biochemical factors and preoperative tumor characteristics predicted lymph node and distant metastasis in the regression model, whereas demographic factors were without effect. The score combining weighted risk factors was: (2×leukocytosis)+(3×thrombocytosis)+(7×elevated CA125)+(4×high-risk histology). The area under curve (AUC) for this total score was 0.823, with 71.6% sensitivity, 75.2% specificity, 25.9% positive predictive value, and 95.7% negative predictive value, using 6 as cut-point. After excluding stage IV carcinomas from the dataset, the AUC was 0.813 for the total score in predicting nodal involvement (P=0.82 vs. total score in predicting stage IIIC–IV carcinomas in the complete dataset). Conclusions Based on the high negative predictive value, this prediction model could be applied for identifying patients who may not benefit from lymphadenectomy for endometrial carcinoma staging.

Published
2013

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

Author

Francesmary Modugno, Alice S. Whittemore, Kunle Odunsi, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Jolanta Lissowska, Malcolm C. Pike, Bu-Tian Ji, Michelle A.T. Hildebrandt, Warren Davis, Agnieszka Dansonka-Mieszkowska, Line Bjørge, Roberta B. Ness, James Paul, Katja K.H. Aben, Nonna Kolomeyevskaya, Melissa C. Southey, Bridget Kruszka, Daniel W. Cramer, Shashikant Lele, Edwin S. Iversen, Kristina Schmitt, Julie M. Cunningham, Xifeng Wu, Celeste Leigh Pearce, Keitaro Matsuo, Cezary Cybulski, Linda E. Kelemen, Kirsten B. Moysich, Kristine G. Wicklund, Ralf Bützow, Shelley S. Tworoger, Grace Friel, Robert P. Edwards, Agnieszka Timorek, Leah Preus, Anna Jakubowska, Paul D.P. Pharoah, Karen Lu, Lambertus A. Kiemeney, Allan Jensen, Elisa V. Bandera, Steven A. Narod, Soo-Hwang Teo, Susanne K. Kjaer, Jonathan Tyrer, Joseph H. Rothstein, Irene Orlow, Rachel Palmieri Weber, Janine M. Joseph, Anna M. van Altena, Mary Nesline, Rüdiger Klapdor, Hannah P. Yang, Graham G. Giles, Pamela J. Thompson, Christine Walsh, Jolanta Kupryjanczyk, Wei Zheng, Nicolas Wentzensen, Angela Brooks-Wilson, Arto Leminen, Philipp Harter, Nadeem Siddiqui, Joanna Moes-Sosnowska, Yin Ling Woo, Anja Rudolph, John R. McLaughlin, Louise A. Brinton, Ingo B. Runnebaum, Shalaka S. Hampras, Linda S. Cook, Lotte Nedergaard, Lara E. Sucheston-Campbell, Natalia Bogdanova, Alexander Hein, Joseph L. Kelley, Claus Høgdall, Matthias Dürst, Jennifer A. Doherty, Ignace Vergote, Argyrios Ziogas, Ian G. Campbell, Prashant Singh, Hoda Anton-Culver, Shan Wang-Gohrke, Helga B. Salvesen, Stefan Nickels, Ingvild L. Tangen, Joe Dennis, Georgia Chenevix-Trench, Eva S. Schernhammer, Paul K. Wallace, Leon F.A.G. Massuger, Lynne R. Wilkens, Ed Dicks, Yukie Bean, Alice W. Lee, Ian McNeish, Evelyn Despierre, Patricia Harrington, Kevin H. Eng, Maria Bisogna, Nhu D. Le, Sandrina Lambrechts, Andrew Berchuck, Honglin Song, Hanis Nazihah Hasmad, Nils Schoof, Diana Eccles, Harvey A. Risch, Xiao-Ou Shu, Rosalind Glasspool, Peter Hillemanns, Jenny Permuth-Wey, Chi-Chen Hong, Catherine M. Phelan, Marc T. Goodman, Peter A. Fasching, Matthias W. Beckmann, Helen Baker, Doug Easton, Robert A. Vierkant, Barbara Perkins, Lene Lundvall, Elizabeth M. Poole, Joanna Plisiecka-Halasa, Arif B. Ekici, Melissa Kellar, Jan Lubinski, Alyssa Clay, Diether Lambrechts, Jacek Gronwald, Keith L. Knutson, Karen Carty, Camilla Krakstad, Jenny Lester, Simon A. Gayther, Ya-Yu Tsai, Rikki Cannioto, Kathryn L. Terry, Ira Schwaab, Susan J. Ramus, Andreas du Bois, Thomas A. Sellers, Estrid Høgdall, Valeria McGuire, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Sara H. Olson, Ellen L. Goode, Song Liu, Usha Menon, Dong Liang, Tanja Pejovic, Yu-Tang Gao, Florian Heitz, Beth Y. Karlan, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Weiva Sieh, Liisa M. Pelttari, Anna H. Wu, Natalia Antonenkova, Satoyo Hosono, Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, endocrine system diseases, Carcinoma, Ovarian Epithelial, T-Lymphocytes, Regulatory, 0302 clinical medicine, STAGE, Gene Frequency, Risk Factors, Genotype, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], immunosuppression, Middle Aged, Protein-Serine-Threonine Kinases, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, Serous fluid, ovarian cancer, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, CARCINOMA, Population, chemical and pharmacologic phenomena, Single-nucleotide polymorphism, FCGR2B, Protein Serine-Threonine Kinases, PERIPHERAL-BLOOD, Biology, DENDRITIC CELLS, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, REGULATORY T-CELLS, education, Aged, Science & Technology, RECEPTOR, Receptor, Transforming Growth Factor-beta Type II, biomarkers, Cell Biology, medicine.disease, 030104 developmental biology, FC-GAMMA-RIIB, Immunology, genetic variation, Cancer research, Ovarian cancer, Receptors, Transforming Growth Factor beta, Clear cell, Priority Research Paper, Adenocarcinoma, Clear Cell
Abstract

Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

36. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author

Joseph L. Kelley, Michelle A.T. Hildebrandt, Diana Eccles, Karen Lu, Elisa V. Bandera, Steven A. Narod, Linda S. Cook, Matthias W. Beckmann, John R. McLaughlin, Liisa M. Pelttari, Elizabeth M. Poole, Arto Leminen, Jennifer A. Doherty, Argyrios Ziogas, Weiva Sieh, Maria Bisogna, Stuart MacGregor, Andrew Berchuck, Agnieszka Timorek, Ralf Bützow, Hoda Anton-Culver, Robert P. Edwards, Peter Hillemanns, Anja Rudolph, Joseph H. Rothstein, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Ignace Vergote, Louise A. Brinton, Meir J. Stampfer, Honglin Song, Jenny Chang-Claude, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Graham G. Giles, Valerie McGuire, Reidun K. Kopperud, Daniel W. Cramer, Alice S. Whittemore, Jacek Gronwald, Gabriel Cuellar-Partida, Georgia Chenevix-Trench, Ellen L. Goode, Stacey J. Winham, Julie M. Cunningham, Estrid Høgdall, Adriaan Vanderstichele, Jan Lubinski, Lukasz Szafron, Peter A. Fasching, Jonathan Tyrer, Alexander Hein, Harvey A. Risch, Ian G. Campbell, Joellen M. Schildkraut, Shelley S. Tworoger, C. Blake Gilks, Allan Jensen, Natalia Bogdanova, Helga B. Salvesen, Rikki Cannioto, Shan Wang-Gohrke, Terry K. Morgan, Susan J. Ramus, Catherine M. Phelan, Kirsten B. Moysich, Usha Menon, Penelope M. Webb, Angela Brooks-Wilson, Ingo B. Runnebaum, Anna H. Wu, Celeste Leigh Pearce, Suzanne C. Dixon, Dong Liang, Yi Lu, Natalia Antonenkova, Diether Lambrechts, Stacey A. Missmer, Brooke L. Fridley, Roberta B. Ness, Mary Anne Rossing, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Marc T. Goodman, Susanne K. Kjaer, Britton Trabert, Kathryn L. Terry, Claus Høgdall, Tomasz Kluz, Heli Nevanlinna, Line Bjørge, Francesmary Modugno, Jolanta Lissowska, Fanny Dao, Simon A. Gayther, Katja K.H. Aben, Leon F.A.G. Massuger, Fiona Bruinsma, Xifeng Wu, Matthias Dürst, Jolanta Kupryjanczyk, Nicolas Wentzensen, Katharina Bischof, Els Van Nieuwenhuysen, Nhu D. Le, and Sara H. Olson

Subjects
0301 basic medicine, endocrine system diseases, Genome-wide association study, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, 0302 clinical medicine, Neoplasms, Ovarian Epithelial, Genotype, Pathology, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Pathology, Molecular, Aetiology, Genetics (clinical), Cancer, Genetics, Ovarian Neoplasms, Genetics & Heredity, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Serous fluid, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Clear cell carcinoma, Female, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Rare Diseases, Complementary and Alternative Medicine, medicine, Humans, Polymorphism, Carcinoma, Human Genome, Molecular, Heritability, medicine.disease, Genetic architecture, 030104 developmental biology, Ovarian cancer
Abstract

Contains fulltext : 171782.pdf (Publisher’s version ) (Closed access) Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 +/- 1.1 %), endometrioid ([Formula: see text] = 3.2 +/- 1.6 %), clear cell ([Formula: see text] = 6.7 +/- 3.3 %) and all EOC ([Formula: see text] = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016

37. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Kenneth Offit, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Christine Maugard, Marco Montagna, Annette Fontaine, Janusz Menkiszak, Robert Winqvist, Pascal Guénel, Rosalind Glasspool, Usha Menon, Daniel Barrowdale, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Martha J. Shrubsole, Lambertus A. Kiemeney, Camilla Krakstad, Dong Liang, Minouk J. Schoemaker, Judith S. Brand, Joseph Vijai, Marc T. Goodman, Thomas A. Sellers, David Van Den Berg, Celeste Leigh Pearce, Alice S. Whittemore, Irene L. Andrulis, Radka Platte, Kunle Odunsi, Orland Diez, Estrid Høgdall, Brooke L. Fridley, C. J. van Asperen, Mary Anne Rossing, Vessela N. Kristensen, Jonathan Tyrer, Tara M. Friebel, Douglas F. Easton, Per Hall, Mads Thomassen, Christine Walsh, Thilo Dörk, Louise A. Brinton, Keith Humphreys, Douglas A. Levine, Allison F. Vitonis, Anna H. Wu, Hermann Brenner, Maria Bisogna, Joellen M. Schildkraut, Maria A. Caligo, Jonine D. Figueroa, Lynne R. Wilkens, Grace Friel, Michael G. Schrauder, Evgeny N. Imyanitov, Sune F. Nielsen, Sylvie Mazoyer, Diana Eccles, Andrew Berchuck, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, Gad Rennert, Arif B. Ekici, Elisa Alducci, Bjarni A. Agnarsson, Linda S. Cook, Javier Benitez, Paolo Peterlongo, Natalia Antonenkova, Annika Lindblom, Patrick Neven, Julia A. Knight, Alan Ashworth, Matti A. Rookus, Frans B. L. Hogervorst, Daniela Zaffaroni, Banu Arun, Sue Healey, Robert P. Edwards, Susanne K. Kjaer, Laura J. van't Veer, John W.M. Martens, Christa Stegmaier, Claudine Isaacs, Daniel W. Cramer, Lars Beckmann, Liisa M. Pelttari, Dieter Flesch-Janys, Irene Orlow, Atocha Romero, Diana Torres, Marjanka K. Schmidt, Simon S. Cross, Alison M. Dunning, Rosemary L. Balleine, Sandra L. Halverson, Benoit Beuselinck, Melissa C. Larson, Senno Verhoef, Jirong Long, Angela Cox, Maartje J. Hooning, Bruce Poppe, Katarzyna Jaworska, Jolanta Kupryjanczyk, Nicolas Wentzensen, Gustavo C. Rodriguez, Tanja Pejovic, Roberta B. Ness, James Paul, Dominique Stoppa-Lyonnet, Nadine Tung, Gianluca Severi, Malcolm C. Pike, Hoda Anton-Culver, Ans M.W. van den Ouweland, Mark E. Robson, Roger L. Milne, Jan C. Oosterwijk, Laima Tihomirova, Helen Tsimiklis, Pierre Laurent-Puig, Florian Heitz, Beth Y. Karlan, Ian Tomlinson, Thérèse Truong, Bernardo Bonanni, Frederik Marmé, Qin Wang, Conxi Lázaro, Volker Arndt, Antoinette Hollestelle, Jacek Gronwald, M. Pilar Zamora, Barbara Wappenschmidt, Maren Weischer, Veli-Matti Kosma, Giulietta Scuvera, Jenny Lester, Andreas Berger, Stephen J. Chanock, Line Bjørge, Anthony J. Swerdlow, Andrew K. Godwin, Mervi Grip, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Paolo Radice, Bent Ejlertsen, Frederieke H. van der Baan, Lothar Haeberle, Valerie McGuire, Kamila Czene, Rob A. E. M. Tollenaar, Maria Soller, Katherine L. Nathanson, Sandrina Lambrechts, Susan J. Ramus, Anja Rudolph, Penny Soucy, Caroline Weltens, Hiltrud Brauch, Olivia Fletcher, Sara H. Olson, Yael Laitman, Marion Piedmonte, Arto Mannermaa, Agnieszka Budzilowska, Olga M. Sinilnikova, Christian F. Singer, Cezary Cybulski, Weiva Sieh, Ed Dicks, Elizabeth J. van Rensburg, Isabel dos Santos Silva, Hans Ehrencrona, Timothy R. Rebbeck, Jaana M. Hartikainen, Sandra Orsulic, Jingmei Li, Carmel Apicella, Anna deFazio, Ian G. Campbell, Ignace Vergote, Rita K. Schmutzler, Fredrick R. Schumacher, Julian Peto, Nadeem Siddiqui, Brian E. Henderson, Starr R. Guzman, Maria Kabisch, John L. Hopper, Arto Leminen, Jeffrey N. Weitzel, Honglin Song, J. Margriet Collée, Ingvild L. Tangen, Børge G. Nordestgaard, Antonis C. Antoniou, Lara Sucheston, Helena C. van Doorn, Lídia Feliubadaló, Leon F.A.G. Massuger, Iain A. McNeish, Nichola Johnson, Simon A. Gayther, Jennifer A. Doherty, Anders Bojesen, Gord Glendon, Yukie Bean, Celine M. Vachon, Barbara Burwinkel, Edith Olah, Shan Wang-Gohrke, Brita Arver, Marc Tischkowitz, Arja Jukkola-Vuorinen, Martin Gore, Vesa Kataja, Nicola Miller, Pamela J. Thompson, Malcolm W.R. Reed, Michelle A.T. Hildebrandt, Ritu Salani, Janet E. Olson, Catriona McLean, Cecilia M. Dorfling, Georgia Chenevix-Trench, Frederique Mariette, Laura Ottini, Fergus J. Couch, Linda E. Kelemen, Nhu D. Le, Michael J. Kerin, Claus Høgdall, Miguel de la Hoya, Jonathan Carter, Mercedes Durán, Inge Søkilde Pedersen, Julie M. Cunningham, Manjeet K. Bolla, Galina Lurie, Loic Le Marchand, Ute Hamann, Muy-Kheng Tea, Karoline Kuchenbaecker, Irene Konstantopoulou, Thomas Hansen, Francesca Damiola, Stefano Fortuzzi, Shelley S. Tworoger, Mikael Eriksson, Carl Blomqvist, Joan Brunet, Allan Jensen, Karen Lu, Elisa V. Bandera, Anne M. van Altena, Anne-Marie Gerdes, Lene Lundvall, Susan L. Neuhausen, Wei Zheng, Ana Osorio, Fiona Bruinsma, Hannah P. Yang, Graham G. Giles, Christoph Engel, Nick Orr, Harvey A. Risch, Jan Lubinski, Jacoba P. Knol-Bout, Phuong L. Mai, Martine Dumont, Xifeng Wu, Christof Sohn, Noah D. Kauff, Kristiina Aittomäki, Natalia Bogdanova, Alexander Hein, Francesmary Modugno, Heli Nevanlinna, Helga B. Salvesen, Adriana Lasa, Daphne Gschwantler Kaulich, Dominiek Smeets, Jenny Permuth-Wey, Josef Herzog, Catherine M. Phelan, Clareann H. Bunker, Steve Ellis, Christopher A. Haiman, Jolanta Lissowska, Judy Garber, Joanna Plisiecka-Halasa, Robert A. Vierkant, Steven A. Narod, Mark H. Greene, Florence Menegaux, Norbert Arnold, Primitiva Menéndez, Robert L. Nussbaum, Katja K.H. Aben, Andreas Schneeweiss, Katri Pylkäs, Els Van Nieuwenhuysen, Tomasz Huzarski, Joe Dennis, Susan M. Domchek, Andreas du Bois, Aleksandra Gentry-Maharaj, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Eitan Friedman, Argyrios Ziogas, Hatef Darabi, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Stig E. Bojesen, Jo Perkins, Raanan Berger, Sharon E. Johnatty, Taru A. Muranen, Montserrat Garcia-Closas, Uffe Birk Jensen, Thomas Brüning, Heiko Müller, Debra Frost, Peter A. Fasching, Lesley McGuffog, Diether Lambrechts, Kelly-Anne Phillips, Caroline M. Seynaeve, Kathryn L. Terry, Ira Schwaab, Ralf Bützow, Manuel R. Teixeira, Joseph H. Rothstein, Bernard Peissel, Anna von Wachenfeldt, Saundra S. Buys, Peter Devilee, Alfons Meindl, Laura Baglietto, Kirsten B. Moysich, Arjen R. Mensenkamp, Philipp Harter, Jacques Simard, Generalitat de Catalunya, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, National Institutes of Health (US), Wellcome Trust, European Commission, National Cancer Institute (US), Medical Oncology, Clinical Genetics, Erasmus MC other, Pediatric Surgery, Pathology, and Neurology

Subjects
0301 basic medicine, Oncology, endocrine system diseases, Endometriosis, Breast cancer, Clinical outcome, Genetic association, KRAS variant, Ovarian cancer, Genome-wide association study, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Prostate, Brjóstakrabbamein, Clinical outcomes, Genotype, Obstetrics and Gynaecology, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PROSTATE, Neoplasms, Glandular and Epithelial, skin and connective tissue diseases, RISK, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics and Gynecology, WOMEN, female genital diseases and pregnancy complications, 3. Good health, medicine.anatomical_structure, Treatment Outcome, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, KRAS, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Breast Neoplasms, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Carcinoma, Humans, GENOME-WIDE ASSOCIATION, Genetic Association Studies, POLYMORPHISMS, Krabbamein, MICRORNA-BINDING-SITE, IDENTIFICATION, business.industry, ENDOMETRIOSIS, Arfgengi, medicine.disease, 030104 developmental biology, PTT12, Eggjastokkar, business
Abstract

Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.

Published
2016

38. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author

Falk Thiel, Simon A. Gayther, Susan Kruger-Kjaer, Matthias Dürst, Robert M Brown, Thilo Doerk, Martin Gore, James M. Flanagan, Ian Tomlinson, Stephen J. Chanock, Thorunn Rafnar, Susan J. Ramus, Brooke L. Fridley, Jonathan Beesley, Jennifer A. Doherty, Tanya Sher, Jan Lubinski, Ya Yu Tsai, Wendy Brewster, Edwin S. Iversen, Evelyn Despierre, Mary Anne Rossing, Jenny Gross, Stanley B. Kaye, Galina Lurie, Natalia Bogdanova, Douglas A. Levine, Peter A. Fasching, Honglin Song, Patrick Sulem, Anna H. Wu, Angela Brooks-Wilson, Ingo B. Runnebaum, Estrid Høgdall, Natalia Antonenkova, Robert P. Edwards, Kara L. Cushing-Haugen, Francesmary Modugno, Ignace Vergote, Søren Besenbacher, Matthias W. Beckmann, Michael J. Birrer, Anna Jakubowska, Paul D.P. Pharoah, Kirsten B. Moyisch, David Van Den Berg, Steven A. Narod, Anne M. van Altena, Lambertus A. Kiemeney, Andrew Berchuck, Daniel W. Cramer, Arto Leminen, Peter Hillemanns, Alice S. Whittemore, Kunle Odunsi, Beth Y. Karlan, Douglas F. Easton, Diether Lambrechts, T A Sellers, Joellen M. Schildkraut, Heli Nevanlinna, Jolanta Lissowska, Kathryn L. Terry, Robert A. Vierkant, Ralf Bützow, Tuomas Heikkinenen, Jan Blaeker, Katja K.H. Aben, Krzysztof Mędrek, Georgia Chenevix-Trench, Weiva Sieh, Leon F.A.G. Massuger, Maria Notaridou, Linda S. Cook, Montserrat Garcia-Closas, Julie A. Baker, Kari Stefansson, Frédéric Amant, Michael E. Carney, Rachel T. Palmieri, Jacek Gronwald, Catherine M. Phelan, Chu Chen, Claus Høgdall, Pamela J. Thompson, Arif B. Ekici, Xiaoqing Chen, Eva Wozniak, Argyrios Ziogas, Aleksandra Gentry-Maharaj, Daniel Paik, Valerie McGuire, Marc T. Goodman, Ian G. Campbell, Hoda Anton-Culver, Shan Wang-Gohrke, Linda E. Kelemen, Jonathan Tyrer, Julie M. Cunningham, Celeste Leigh Pearce, Penelope M. Webb, Rebecca Hein, Dena G. Hernandez, Kelly L. Bolton, Chris Jones, Patricia G. Moorman, Joanne B. Weidhaas, Nhu D. Le, Daniel O. Stram, Roberta B. Ness, James Paul, Hanna P. Yang, Richard S. Houlston, Ellen L. Goode, Sharon E. Johnatty, and Jenny Chang-Claude

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, MEDLINE, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, Genetics, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genome, Human, Published Erratum, Gene Expression Profiling, Ovary, Middle Aged, medicine.disease, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Endometrial Neoplasms, 030104 developmental biology, Case-Control Studies, Female, Ovarian cancer, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Genome-Wide Association Study
Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Published
2016

39. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study

Author

Liisa M. Pelttari, Joseph L. Kelley, Adriaan Vanderstichele, Jue-Sheng Ong, Jonathan Tyrer, Linda S. Cook, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Ellen L. Goode, Fiona Bruinsma, Roberta B. Ness, Daniel W. Cramer, Francesmary Modugno, Penelope M. Webb, C. Blake Gilks, Britton Trabert, Jacek Gronwald, Diana Eccles, Georgia Chenevix-Trench, Fanny Dao, Michelle A.T. Hildebrandt, Graham G. Giles, Gabriel Cuellar-Partida, Julie M. Cunningham, Puya Gharahkhani, Celeste Leigh Pearce, Usha Menon, Maria Bisogna, Estrid Høgdall, Shelley S. Tworoger, Allan Jensen, Alexander Hein, Matthias W. Beckmann, Anna Jakubowska, Paul D.P. Pharoah, Xifeng Wu, Valerie McGuire, Dong Liang, Robert P. Edwards, Joellen M. Schildkraut, Catherine M. Phelan, John R. McLaughlin, Arto Leminen, Heli Nevanlinna, Stacey A. Missmer, Brooke L. Fridley, Angela Brooks-Wilson, Ingo B. Runnebaum, Lambertus A. Kiemeney, Elizabeth M. Poole, Yi-chen Lu, Jolanta Lissowska, Jennifer A. Doherty, Ian G. Campbell, Susanne K. Kjaer, Mary Anne Rossing, Stuart MacGregor, Argyrios Ziogas, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Claus Høgdall, Jolanta Kupryjanczyk, Kirsten B. Moysich, Nicolas Wentzensen, Katja K.H. Aben, Shan Wang-Gohrke, Katharina Bischof, Reidun K. Kopperud, Alice S. Whittemore, Hoda Anton-Culver, Ursula Eilber, Karen Lu, Elisa V. Bandera, Line Bjørge, Simon A. Gayther, Rikki Cannioto, Honglin Song, Els Van Nieuwenhuysen, Susan J. Ramus, Louise A. Brinton, Steven A. Narod, Meir J. Stampfer, Anja Rudolph, Ignace Vergote, Matthias Dürst, Andrew Berchuck, Peter Hillemanns, Rachel E. Neale, Aleksandra Gentry-Maharaj, Lukasz Szafron, Harvey A. Risch, Jenny Chang-Claude, Terry K. Morgan, Marc T. Goodman, Natalia Bogdanova, Helga B. Salvesen, Weiva Sieh, Ralf Bützow, Peter A. Fasching, Joseph H. Rothstein, Agnieszka Timorek, Nhu D. Le, Diether Lambrechts, Anna H. Wu, Natalia Antonenkova, Stacey J. Winham, Jan Lubinski, Kathryn L. Terry, Tomasz Kluz, and Leon F.A.G. Massuger

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mendelian Randomization, Risk Factors, Internal medicine, Mendelian randomization, medicine, Vitamin D and neurology, Odds Ratio, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Vitamin D, Ovarian Neoplasms, Cancer prevention, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Confounding, Statistics, Cancer, General Medicine, Odds ratio, Mendelian Randomization Analysis, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Public Health and Health Services, Female, business, Ovarian cancer
Abstract

Contains fulltext : 171904.pdf (Publisher’s version ) (Closed access) BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

40. A Finnish founder mutation inRAD51D: analysis in breast, ovarian, prostate, and colorectal cancer: Table 1

Author

Anne Kallioniemi, Ralf Bützow, Lauri A. Aaltonen, Liisa M. Pelttari, Päivi Heikkilä, Riikka Nurminen, Heli Nevanlinna, Carl Blomqvist, Johanna Schleutker, Johanna I. Kiiski, Alexandra E. Gylfe, Kristiina Aittomäki, and Arto Leminen

Subjects
Genetics, Oncology, education.field_of_study, medicine.medical_specialty, Colorectal cancer, business.industry, Population, Cancer, medicine.disease, Penetrance, Prostate cancer, Breast cancer, Germline mutation, Internal medicine, medicine, Ovarian cancer, education, business, Genetics (clinical)
Abstract

Background RAD51D and RAD54L are involved in homologous recombination, and rare mutations in RAD51D were recently found in breast-ovarian cancer families. This study investigated RAD51D and RAD54L for mutations in breast and ovarian cancer patients in the Finnish population. Methods The study sequenced the RAD51D and RAD54L genes in 95 breast and/or ovarian cancer families and genotyped the identified mutation in an additional 2200 breast and 553 ovarian cancer patients and 2102 population controls. To investigate the role of the mutation in other common cancers, 1094 prostate and 980 colorectal cancer patients were genotyped. Results In the screening of RAD51D , one deleterious founder mutation c.576+1G>A was identified in two breast-ovarian cancer families. No mutations were found in RAD54L . Altogether, the c.576+1G>A mutation was detected in 5/707 patients with a personal or family history of ovarian cancer (OR 9.16, 95% CI 1.07 to 78.56; p=0.024), with the highest frequency among breast-ovarian cancer families (3/105 vs 1/1287 controls, OR 37.82, 95% CI 3.90 to 366.91; p=0.0016), but no elevated frequency among breast cancer patients/families (2/2105, p=1). The mutation was not found among prostate or colorectal cancer patients. Conclusions The results of this study on familial and unselected breast, ovarian, colorectal, and prostate cancer patients suggest that RAD51D is primarily a moderate penetrance susceptibility gene for ovarian cancer, with clinical significance for the carriers.

Published
2012

41. 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

42. Serum Vascular Endothelial Growth Factor A (VEGF) Is Elevated in Patients with Ovarian Granulosa Cell Tumor (GCT), and VEGF Inhibition by Bevacizumab Induces Apoptosis in GCTin Vitro

Author

Anniina Färkkilä, Ralf Bützow, Mikko Anttonen, Arto Leminen, Markku Heikinheimo, Hanna Tauriala, Marjut Pihlajoki, and Leila Unkila-Kallio

Subjects
Adult, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Ovarian Granulosa Cell, Bevacizumab, Angiogenesis, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Angiogenesis Inhibitors, Apoptosis, Cell Count, Biology, Antibodies, Monoclonal, Humanized, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cell Line, Tumor, Internal medicine, Tumor Cells, Cultured, medicine, Humans, Aged, Granulosa Cell Tumor, 030304 developmental biology, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, Biochemistry (medical), Kinase insert domain receptor, Middle Aged, Endostatins, 3. Good health, Angiogenesis inhibitor, Vascular endothelial growth factor A, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, Female, Endostatin, medicine.drug
Abstract

Ovarian granulosa cell tumors (GCT) are highly vascularized and express vascular endothelial growth factor A (VEGF) and its functional receptor VEGF receptor 2 (VEGFR-2). Angiogenesis inhibitors have been used in the treatment of ovarian carcinomas, whereas their roles in GCT remain unknown.The aim was to assess serum levels of VEGF and endostatin, an endogenous angiogenesis inhibitor, in GCT patients and to study the effect of bevacizumab (BVZ), a VEGF-binding monoclonal antibody, on human GCT cells in vitro.Using ELISA, we measured soluble VEGF and endostatin in the sera of 54 GCT patients and in conditioned media from cultures of 14 primary GCT and an established GCT cell line (KGN). The expression of activated VEGFR-2 was analyzed in GCT tissues using immunohistochemistry. GCT cells were treated with BVZ and analyzed for cell number and apoptosis.Serum VEGF was elevated in GCT patients, and the levels significantly decreased after tumor removal (P0.05), whereas serum endostatin levels changed conversely. Human GCT expressed activated VEGFR-2 protein, and the level of expression was associated with tumor VEGF and vascularization. In addition, the cultured GCT cells produced significant amounts of VEGF but not endostatin. Treatment of KGN cells with BVZ significantly reduced the number of viable cells by 41% and induced a 3.3-fold increase in apoptosis. Furthermore, BVZ induced a mean 2.6-fold increase in apoptosis in six primary GCT cell cultures studied.These data suggest an autocrine role for VEGF in GCT and encourage clinical studies on anti-VEGF treatments in this disease.

Published
2011

43. Prognostic role of CIP2A expression in serous ovarian cancer

Author

Jukka Westermarck, Heini Lassus, Ari Ristimäki, Caj Haglund, Ralf Bützow, Annabrita Hemmes, Camilla Böckelman, and Arto Leminen

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Cytoplasm, endocrine system diseases, Serous carcinoma, Colorectal cancer, Immunoblotting, Biology, survival, Autoantigens, CIP2A, Cohort Studies, Immunoenzyme Techniques, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Carcinoma, Biomarkers, Tumor, Humans, Molecular Diagnostics, 030304 developmental biology, Retrospective Studies, grade, Ovarian Neoplasms, 0303 health sciences, Intracellular Signaling Peptides and Proteins, Cancer, Membrane Proteins, Middle Aged, medicine.disease, Prognosis, Head and neck squamous-cell carcinoma, female genital diseases and pregnancy complications, 3. Good health, Cystadenocarcinoma, Serous, ErbB Receptors, Survival Rate, Serous fluid, ovarian cancer, Oncology, Tissue Array Analysis, 030220 oncology & carcinogenesis, Cancer research, Female, Ovarian cancer
Abstract

Ovarian cancer is the sixth most common cancer in women and the second most common gynaecological malignancy in the world. Incidence rates have increased slowly in developed countries, with an incidence rate of 9 per 100 000 (Parkin et al, 2005). Five-year survival is less than 50% for ovarian cancer patients, as most cases are found at an advanced stage (Jemal et al, 2008). The standard treatment is extensive surgery usually followed by chemotherapy. Ovarian surface epithelium and tubal tissue have been proposed to represent the origins of ovarian cancer, of which the most frequent subtype is serous carcinoma (Dubeau, 2008). Ovarian cancer can be divided into two subgroups: type I tumours that are slowly developing low-grade serous, mucinous, endometriod, and clear-cell carcinomas, whereas type II tumours are rapidly progressing high-grade serous or undifferentiated carcinomas (Levanon et al, 2008). Precursor lesions of the type II ovarian cancers are poorly understood and prognosis is poor. This type of ovarian tumours also more commonly harbour mutations in the p53 gene and show a high proliferation index (Shih and Kurman, 2004; Landen et al, 2008). Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein overexpressed in head and neck squamous cell carcinoma and in colon cancer (Junttila and Westermarck, 2007; Junttila et al, 2007; Mumby, 2007). CIP2A interacts with PP2A and prevents PP2A-mediated dephosphorylation of the oncogene c-Myc (Junttila et al, 2007). CIP2A is a marker of reduced overall survival in certain subgroups of gastric cancer (Khanna et al, 2009), and its expression associates with high grade and lymph node metastasis in breast cancer (Come et al, 2009). Its role in ovarian carcinogenesis is, however, unknown. To address the role of CIP2A in ovarian cancer, we investigated the association of CIP2A protein expression to clinicopathological variables and molecular markers in serous ovarian cancer.

Published
2011

44. Aurora-A overexpression and aneuploidy predict poor outcome in serous ovarian carcinoma

Author

Heini Lassus, Jorma Isola, Ralf Bützow, Synnöve Staff, and Arto Leminen

Subjects
Oncology, Cytoplasm, medicine.medical_specialty, DNA Copy Number Variations, Proliferation index, Aneuploidy, macromolecular substances, Protein Serine-Threonine Kinases, Biology, Polymerase Chain Reaction, Aurora Kinases, Internal medicine, Ovarian carcinoma, Chromosome instability, medicine, Humans, RNA, Messenger, Phosphorylation, Cystadenocarcinoma, CISH, In Situ Hybridization, Neoplasm Staging, Cell Nucleus, Ovarian Neoplasms, Obstetrics and Gynecology, DNA, Neoplasm, medicine.disease, Immunohistochemistry, Cystadenocarcinoma, Serous, enzymes and coenzymes (carbohydrates), Serous fluid, Multivariate Analysis, embryonic structures, Female, biological phenomena, cell phenomena, and immunity, Ovarian cancer
Abstract

Objective Aurora-A is a potential oncogene and therapeutic target in ovarian carcinoma. It is involved in mitotic events and overexpression leads to centrosome amplification and chromosomal instability. The objective of this study was to evaluate the clinical significance of Aurora-A and DNA ploidy in serous ovarian carcinoma. Methods Serous ovarian carcinomas were analysed for Aurora-A protein by immunohistochemistry ( n =592), Aurora-A copy number by CISH ( n =169), Aurora-A mRNA by real-time PCR ( n =158) and DNA ploidy by flowcytometry ( n =440). Results Overexpression of Aurora-A was found in 27% of the tumors, cytoplasmic overexpression in 11% and nuclear in 17%. The cytoplasmic and nuclear overexpression were nearly mutually exclusive. Both cytoplasmic and nuclear overexpression were associated with shorter survival, high grade, high proliferation index and aberrant p53. Interestingly, only cytoplasmic expression was associated with aneuploidy and expression of phosphorylated Aurora-A. DNA ploidy was associated with poor patient outcome as well as aggressive clinicopathological parameters. In multivariate analysis, Aurora-A overexpression appeared as an independent prognostic factor for disease-free survival, together with grade, stage and ploidy. Conclusions Aurora-A protein expression is strongly linked with poor patient outcome and aggressive disease characteristics, which makes Aurora-A a promising biomarker and a potential therapeutic target in ovarian carcinoma. Cytoplasmic and nuclear Aurora-A protein may have different functions. DNA aneuploidy is a strong predictor of poor prognosis in serous ovarian carcinoma.

Published
2011

45. Immunohistochemical studies on uterine carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma: expression and prognostic importance of ten different markers

Author

Riitta Koivisto-Korander, Arto Leminen, Ralf Bützow, and Anna-Maija Koivisto

Subjects
Adult, Leiomyosarcoma, Pathology, medicine.medical_specialty, Progesterone receptor A, Sarcoma, Endometrial Stromal, Biology, Carcinosarcoma, Biomarkers, Tumor, medicine, Humans, Uterine Neoplasm, Survival rate, Aged, Aged, 80 and over, Endometrial stromal sarcoma, Uterine sarcoma, Estrogen Receptor alpha, General Medicine, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Endometrial Neoplasms, Survival Rate, Uterine Neoplasms, Female, Sarcoma, Tumor Suppressor Protein p53, Receptors, Progesterone
Abstract

Uterine sarcomas are rare and aggressive gynecologic malignancies. In this immunohistochemical (IHC) study, expression of Ki-67, p53, CD10, CD44, desmin, smooth muscle actin, estrogen receptor α (ERα), androgen receptor (AR), progesterone receptor A (PRA), and c-kit and their influence on survival in cases of uterine carcinosarcoma (CS), leiomyosarcoma (LMS), and endometrial stromal sarcoma (ESS) were evaluated. Medical records were reviewed and data collected concerning all uterine sarcomas treated during a 12-year period at Helsinki University Central Hospital. There was sufficient histological material for IHC analysis and slide review in 67 cases. Survival analysis was performed using the Kaplan-Meier method, and median survival times with 95% confidence intervals are given. Survival in cases of LMS was statistically significantly affected by the expression of p53, ERα, and PRA. Striking differences in expression of IHC markers when comparing results with those in earlier studies were the absence of AR immunoreactivity in all uterine sarcomas and low incidence of c-kit (15%; in endometrial stromal sarcoma). None of the markers was statistically significantly associated with survival of ESS and CS patients. The expression of p53, ERα, and PRA in uterine LMS may give prognostic information concerning the behavior of the disease. Hormonal therapy could be recommended as a treatment option in cases of hormone receptor-positive LMS.

Published
2010

46. Costs and health-related quality of life effects of hysterectomy in patients with benign uterine disorders

Author

Harri Sintonen, Arto Leminen, Anne Heikkilä, Kaisa Taipale, Anna-Maija Tapper, Pirjo Räsänen, and Risto O. Roine

Subjects
Adult, Pediatrics, medicine.medical_specialty, Cost-Benefit Analysis, medicine.medical_treatment, Population, Hysterectomy, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Humans, Medicine, Prospective Studies, 030212 general & internal medicine, education, Prospective cohort study, Aged, Uterine Diseases, education.field_of_study, 030219 obstetrics & reproductive medicine, business.industry, Age Factors, Obstetrics and Gynecology, General Medicine, Middle Aged, medicine.disease, 3. Good health, Surgery, Quality-adjusted life year, Menopause, Life expectancy, Female, Observational study, Quality-Adjusted Life Years, business
Abstract

To gain knowledge about the utility of hysterectomy in a real-world setting and to relate the utility of the intervention to its costs.Prospective observational study.University referral hospital in Helsinki.A total of 337 women entering for routine hysterectomy due to a benign disease (210 benign uterine or ovarian cause, 20 endometriosis, 51 uterovaginal prolapse, 56 menorrhagia).Patients filled in the 15D health-related quality of life (HRQoL) questionnaire before and six months after the operation. Costs were examined from the perspective of secondary care provider. Benefits of surgery were extrapolated till the end of remaining statistical life expectancy of each woman in the prolapse group and until menopause in the other groups.HRQoL and cost per quality-adjusted life year (QALY) gained.Mean [standard deviation (SD)] HRQoL score (on a 0-1 scale) in the whole group improved from the preoperative of 0.905 (0.073) to 0.925 (0.077) six months after the operation (p0.001). The largest mean (SD) improvement was seen in patients with endometriosis [0.048 (0.067)] followed by those with menorrhagia [0.024 (0.054)], benign uterine or ovarian cause [0.018 (0.071)], and prolapse [0.017 (0.055)]. In the whole group, the intervention produced a mean (SD) of 0.222 (1.270) QALYs at mean (SD) direct hospital cost of euro3,138 (2,098). Consequently, the cost per QALY gained in the whole group was euro14,135 varying from euro3,720 to 31,570 in the disease groups.The cost per QALY gained for hysterectomy for benign uterine disorders is strongly dependent on the indication for surgery.

Published
2009

47. Biweekly docetaxel in recurrent ovarian cancer: a phase I dose finding study

Author

Arto Leminen and Johanna Mäenpää

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Docetaxel, Neutropenia, Toxicology, Gastroenterology, Sepsis, Stable Disease, Internal medicine, medicine, Humans, Pharmacology (medical), Aged, Neoplasm Staging, Ovarian Neoplasms, Pharmacology, Dose-Response Relationship, Drug, business.industry, Cancer, Middle Aged, Prognosis, medicine.disease, Cystadenocarcinoma, Serous, Granulocyte colony-stimulating factor, Survival Rate, Treatment Outcome, Toxicity, Female, Taxoids, Neoplasm Recurrence, Local, business, Carcinoma, Endometrioid, Febrile neutropenia, medicine.drug
Abstract

To determine the maximum tolerated dose of biweekly docetaxel in patients with recurrent ovarian cancer, aiming at 70 mg/m(2).In this phase I trial, 8 patients were treated with biweekly docetaxel 50-65 mg/m(2). Dose-limiting toxicities were defined as any grade 3-4 non-hematological toxicity, prolonged (or =1 week) grade 4 neutropenia or platelet count25 x 10(9)/L, any neutropenic sepsis or febrile neutropenia, or any grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding.Two groups of 3 patients each were given docetaxel 50 and 60 mg/m(2), respectively, and 2 patients received 65 mg/m(2). A total of 43 cycles were given; 26% of these were delayed, while granulocyte colony stimulating factor (G-CSF) support was used in 33%. The main toxicity was neutropenia: at dose levels of 50, 60, and 65 mg/m(2), grade 3-4 neutropenia occurred in 2/3, 3/3 and 1/2 patients, respectively. One patient experienced febrile neutropenia. A dose reduction was needed in 6 out of 13 cycles at the 65 mg/m(2) dose level. The study had to be closed prematurely due to the frequent need for G-CSF support, precluding the exploration of the 70 mg/m(2) dose. Non-hematological toxicities were mild. One patient had a partial response and six patients showed a stable disease.The maximum tolerated dose of biweekly docetaxel could not be determined in this study. It seems that increasing the dose beyond 60 mg/m(2) without a routine use of G-CSF is difficult.

Published
2008

48. GATA-4 Regulates Bcl-2 Expression in Ovarian Granulosa Cell Tumors

Author

Antti Kyrönlahti, Ralf Bützow, Maarit Rämö, Leila Unkila-Kallio, Nafis A. Rahman, Ilpo Huhtaniemi, Maija Tamminen, Mona Nemer, Mikko Anttonen, Markku Heikinheimo, and Arto Leminen

Subjects
Adult, medicine.medical_specialty, Ovarian Granulosa Cell, Cyclin D, Granulosa cell, Cyclin B, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cyclin D2, Cyclins, Internal medicine, Chlorocebus aethiops, medicine, Animals, Humans, Cells, Cultured, Aged, Granulosa Cell Tumor, 030304 developmental biology, Cyclin, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, Cell growth, Middle Aged, Cell cycle, GATA4 Transcription Factor, Genes, bcl-2, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, COS Cells, biology.protein, Female
Abstract

Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the antiapoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2, and cyclin D2, and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2, and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays, and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression up-regulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2.

Published
2008

49. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

Author

Pangiotis Alexiou, Molly Megraw, Kosei Hasegawa, Barbara L. Weber, George Coukos, Heini Lassus, Cameron N. Johnstone, Yoshio Naomoto, Antonis Giannakakis, Phyllis A. Gimotty, Raphael Sandaltzopoulos, Angela DeMichele, Joel Greshock, Praveen Sethupathy, Dionyssios Katsaros, Shun Liang, Jia Huang, George A. Calin, Anil K. Rustgi, Michael J. Birrer, Sarah Adams, Victor A. Simossis, Chang Gong Liu, Qihong Huang, Tomas Bonome, Sippy Kaur, Ralf Bützow, Carlo M. Croce, Artemis G. Hatzigeorgiou, Stefano Volinia, Arto Leminen, Nuo Yang, and Lin Zhang

Subjects
Ribonuclease III, Down-Regulation, Dlk1-Gtl2 domain, Noncoding RNA, Genetics, Multidisciplinary, Biology, NO, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, microRNA, medicine, Humans, Gene silencing, RNA, Messenger, Epigenetics, Neoplasm Staging, 030304 developmental biology, Ovarian Neoplasms, Regulation of gene expression, 0303 health sciences, Genome, Human, Gene Expression Profiling, Cancer, Epithelial Cells, DNA, Neoplasm, Biological Sciences, medicine.disease, Non-coding RNA, Survival Analysis, Gene Expression Regulation, Neoplastic, Gene expression profiling, MicroRNAs, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, Female
Abstract

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray ( n = 106), array-based comparative genomic hybridization ( n = 109), cDNA microarray ( n = 76), and tissue array ( n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of ≈15% and at least ≈36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster ( Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

Published
2008

50. Updating on primary fallopian tube carcinoma

Author

Annika Riska and Arto Leminen

Subjects
Oncology, medicine.medical_specialty, Fallopian tube carcinoma, Chorionic Gonadotropin, Breast cancer, Internal medicine, medicine, Fallopian Tube Neoplasms, Humans, Risk factor, Lung cancer, Aged, Gynecology, business.industry, Incidence (epidemiology), Obstetrics and Gynecology, Cancer, General Medicine, Middle Aged, Prognosis, medicine.disease, medicine.anatomical_structure, Trypsin Inhibitor, Kazal Pancreatic, CA-125 Antigen, Female, Ovarian cancer, business, Fallopian tube
Abstract

Primary fallopian tube carcinoma (PFTC) is rare, constituting about 1% of female genital tract malignancies, and little is known about its etiological, protective, risk or prognostic factors. Earlier, such factors were thought to be similar to those seen in ovarian cancer. The incidence of PFTC has been rising during the last decades, especially in higher social classes and among women in certain occupations. Parity is a strong protective factor for PFTC, with a lower incidence associated with an increasing number of deliveries. Previous sterilisation seems to offer some protection. Earlier suggestions of previous genital infections as risk factors appear not to hold. Previous cancers are frequent among PFTC patients, especially breast cancer. Second primary cancers after PFTC are also frequent, especially non-lymphoid leukemia, colorectal, breast, bladder and lung cancer. Only 4% of primary fallopian carcinomas are correctly diagnosed before operation. Treatment consists of aggressive cytoreductive surgery and adjuvant chemotherapy with a platinum-taxane combination. A high preoperative serum hCGss is a strong prognostic factor for worse prognosis. The 5-year survival rates vary between 22 and 57%.

Published
2007

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