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6 results on '"Inge Sokilde Pedersen"'

1. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Author

Elena Vigorito, Karoline B Kuchenbaecker, Jonathan Beesley, Julian Adlard, Bjarni A Agnarsson, Irene L Andrulis, Banu K Arun, Laure Barjhoux, Muriel Belotti, Javier Benitez, Andreas Berger, Anders Bojesen, Bernardo Bonanni, Carole Brewer, Trinidad Caldes, Maria A Caligo, Ian Campbell, Salina B Chan, Kathleen B M Claes, David E Cohn, Jackie Cook, Mary B Daly, Francesca Damiola, Rosemarie Davidson, Antoine de Pauw, Capucine Delnatte, Orland Diez, Susan M Domchek, Martine Dumont, Katarzyna Durda, Bernd Dworniczak, Douglas F Easton, Diana Eccles, Christina Edwinsdotter Ardnor, Ros Eeles, Bent Ejlertsen, Steve Ellis, D Gareth Evans, Lidia Feliubadalo, Florentia Fostira, William D Foulkes, Eitan Friedman, Debra Frost, Pragna Gaddam, Patricia A Ganz, Judy Garber, Vanesa Garcia-Barberan, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Sophie Giraud, Andrew K Godwin, David E Goldgar, Christopher R Hake, Thomas V O Hansen, Sue Healey, Shirley Hodgson, Frans B L Hogervorst, Claude Houdayer, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Lauren Jacobs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M John, Joseph Vijai, Beth Y Karlan, Karin Kast, KConFab Investigators, Sofia Khan, Ava Kwong, Yael Laitman, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jan Lubinski, Phuong L Mai, Siranoush Manoukian, Sylvie Mazoyer, Alfons Meindl, Arjen R Mensenkamp, Marco Montagna, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Edith Olah, Olufunmilayo I Olopade, Kai-Ren Ong, Ana Osorio, Sue Kyung Park, Ylva Paulsson-Karlsson, Inge Sokilde Pedersen, Bernard Peissel, Paolo Peterlongo, Georg Pfeiler, Catherine M Phelan, Marion Piedmonte, Bruce Poppe, Miquel Angel Pujana, Paolo Radice, Gad Rennert, Gustavo C Rodriguez, Matti A Rookus, Eric A Ross, Rita Katharina Schmutzler, Jacques Simard, Christian F Singer, Thomas P Slavin, Penny Soucy, Melissa Southey, Doris Steinemann, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Csilla I Szabo, Muy-Kheng Tea, Manuel R Teixeira, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Athanassios Vratimos, Jeffrey N Weitzel, Lesley McGuffog, Judy Kirk, Amanda Ewart Toland, Ute Hamann, Noralane Lindor, Susan J Ramus, Mark H Greene, Fergus J Couch, Kenneth Offit, Paul D P Pharoah, Georgia Chenevix-Trench, and Antonis C Antoniou

Subjects
Medicine, Science
Abstract

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Published
2016
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2. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Author

Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Vernon S Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Català, Joan Brunet, Lidia Feliubadaló, Eva Tornero, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K Arun, Amanda E Toland, Beth Y Karlan, Christine Walsh, Jenny Lester, Mark H Greene, Phuong L Mai, Robert L Nussbaum, Irene L Andrulis, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Rosa B Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom Van Maerken, Orland Díez, Thomas V Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de la Hoya, Trinidad Caldés, Alison M Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R Teixeira, Teixeira, Frans B L Hogervorst, Annemarie H van der Hout, Caroline Seynaeve, Rob B van der Luijt, Marjolijn J L Ligtenberg, Peter Devilee, Juul T Wijnen, Matti A Rookus, Hanne E J Meijers-Heijboer, Marinus J Blok, Ans M W van den Ouweland, Cora M Aalfs, Gustavo C Rodriguez, Kelly-Anne A Phillips, Marion Piedmonte, Stacy R Nerenstone, Victoria L Bae-Jump, David M O'Malley, Elena S Ratner, Rita K Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A Kruse, Lenka Foretova, Paolo Peterlongo, Loris Bernard, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Andreas Berger, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, BCFR, Esther M John, Alex Miron, Susan L Neuhausen, Mary Beth Terry, Wendy K Chung, Mary B Daly, David E Goldgar, Ramunas Janavicius, Cecilia M Dorfling, Elisabeth J van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Andrew K Godwin, Edith Olah, Steven A Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, SWE-BRCA, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N Imyanitov, Ute Hamann, kConFab Investigators, Amanda B Spurdle, Sue Healey, Jeffrey N Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, GEMO, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M Sinilnikova, Christopher A Maxwell, Joseph Vijai, Mark Robson, Noah Kauff, Marina J Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F Easton, Kenneth Offit, Georgia Chenevix-Trench, Fergus J Couch, Antonis C Antoniou, and Miguel Angel Pujana

Subjects
Medicine, Science
Abstract

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Published
2015
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3. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Ana Osorio, Roger L Milne, Karoline Kuchenbaecker, Tereza Vaclová, Guillermo Pita, Rosario Alonso, Paolo Peterlongo, Ignacio Blanco, Miguel de la Hoya, Mercedes Duran, Orland Díez, Teresa Ramón Y Cajal, Irene Konstantopoulou, Cristina Martínez-Bouzas, Raquel Andrés Conejero, Penny Soucy, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, SWE-BRCA, Brita Arver, Johanna Rantala, Niklas Loman, Hans Ehrencrona, Olufunmilayo I Olopade, Mary S Beattie, Susan M Domchek, Katherine Nathanson, Timothy R Rebbeck, Banu K Arun, Beth Y Karlan, Christine Walsh, Jenny Lester, Esther M John, Alice S Whittemore, Mary B Daly, Melissa Southey, John Hopper, Mary B Terry, Saundra S Buys, Ramunas Janavicius, Cecilia M Dorfling, Elizabeth J van Rensburg, Linda Steele, Susan L Neuhausen, Yuan Chun Ding, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Mar Infante, Belén Herráez, Leticia Thais Moreno, Jeffrey N Weitzel, Josef Herzog, Kisa Weeman, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Bernardo Bonanni, Frederique Mariette, Sara Volorio, Alessandra Viel, Liliana Varesco, Laura Papi, Laura Ottini, Maria Grazia Tibiletti, Paolo Radice, Drakoulis Yannoukakos, Judy Garber, Steve Ellis, Debra Frost, Radka Platte, Elena Fineberg, Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Diana Eccles, Jackie Cook, Shirley Hodgson, Carole Brewer, Marc Tischkowitz, Fiona Douglas, Mary Porteous, Lucy Side, Lisa Walker, Patrick Morrison, Alan Donaldson, John Kennedy, Claire Foo, Andrew K Godwin, Rita Katharina Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Bruce Poppe, Kathleen Claes, Marion Piedmonte, Kathy Tucker, Floor Backes, Gustavo Rodríguez, Wendy Brewster, Katie Wakeley, Thomas Rutherford, Trinidad Caldés, Heli Nevanlinna, Kristiina Aittomäki, Matti A Rookus, Theo A M van Os, Lizet van der Kolk, J L de Lange, Hanne E J Meijers-Heijboer, A H van der Hout, Christi J van Asperen, Encarna B Gómez Garcia, Nicoline Hoogerbrugge, J Margriet Collée, Carolien H M van Deurzen, Rob B van der Luijt, Peter Devilee, HEBON, Edith Olah, Conxi Lázaro, Alex Teulé, Mireia Menéndez, Anna Jakubowska, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Oskar Th Johannsson, Christine Maugard, Marco Montagna, Silvia Tognazzo, Manuel R Teixeira, Sue Healey, KConFab Investigators, Curtis Olswold, Lucia Guidugli, Noralane Lindor, Susan Slager, Csilla I Szabo, Joseph Vijai, Mark Robson, Noah Kauff, Liying Zhang, Rohini Rau-Murthy, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Catherine M Phelan, Mark H Greene, Phuong L Mai, Flavio Lejbkowicz, Irene Andrulis, Anna Marie Mulligan, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Mads Thomassen, Torben A Kruse, Uffe Birk Jensen, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Jacques Simard, Douglas F Easton, Kenneth Offit, Fergus J Couch, Georgia Chenevix-Trench, Antonis C Antoniou, and Javier Benitez

Subjects
Genetics, QH426-470
Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p

Published
2014
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4. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

Author

Fergus J Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, Mia M Gaudet, Ed Dicks, Matthew Kosel, Sue Healey, Olga M Sinilnikova, Adam Lee, François Bacot, Daniel Vincent, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, Anna Jakubowska, kConFab Investigators, Paolo Radice, Rita Katharina Schmutzler, SWE-BRCA, Susan M Domchek, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Ontario Cancer Genetics Network, Thomas V O Hansen, Susan L Neuhausen, Csilla I Szabo, Ignacio Blanco, Mark H Greene, Beth Y Karlan, Judy Garber, Catherine M Phelan, Jeffrey N Weitzel, Marco Montagna, Edith Olah, Irene L Andrulis, Andrew K Godwin, Drakoulis Yannoukakos, David E Goldgar, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Mary Beth Terry, Mary B Daly, Elizabeth J van Rensburg, Ute Hamann, Susan J Ramus, Amanda Ewart Toland, Maria A Caligo, Olufunmilayo I Olopade, Nadine Tung, Kathleen Claes, Mary S Beattie, Melissa C Southey, Evgeny N Imyanitov, Marc Tischkowitz, Ramunas Janavicius, Esther M John, Ava Kwong, Orland Diez, Judith Balmaña, Rosa B Barkardottir, Banu K Arun, Gad Rennert, Soo-Hwang Teo, Patricia A Ganz, Ian Campbell, Annemarie H van der Hout, Carolien H M van Deurzen, Caroline Seynaeve, Encarna B Gómez Garcia, Flora E van Leeuwen, Hanne E J Meijers-Heijboer, Johannes J P Gille, Margreet G E M Ausems, Marinus J Blok, Marjolijn J L Ligtenberg, Matti A Rookus, Peter Devilee, Senno Verhoef, Theo A M van Os, Juul T Wijnen, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Louise Izatt, Rosalind A Eeles, Julian Adlard, Diana M Eccles, Jackie Cook, Carole Brewer, Fiona Douglas, Shirley Hodgson, Patrick J Morrison, Lucy E Side, Alan Donaldson, Catherine Houghton, Mark T Rogers, Huw Dorkins, Jacqueline Eason, Helen Gregory, Emma McCann, Alex Murray, Alain Calender, Agnès Hardouin, Pascaline Berthet, Capucine Delnatte, Catherine Nogues, Christine Lasset, Claude Houdayer, Dominique Leroux, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Hagay Sobol, Isabelle Coupier, Laurence Venat-Bouvet, Laurent Castera, Marion Gauthier-Villars, Mélanie Léoné, Pascal Pujol, Sylvie Mazoyer, Yves-Jean Bignon, GEMO Study Collaborators, Elżbieta Złowocka-Perłowska, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska, Tomasz Huzarski, Amanda B Spurdle, Alessandra Viel, Bernard Peissel, Bernardo Bonanni, Giulia Melloni, Laura Ottini, Laura Papi, Liliana Varesco, Maria Grazia Tibiletti, Paolo Peterlongo, Sara Volorio, Siranoush Manoukian, Valeria Pensotti, Norbert Arnold, Christoph Engel, Helmut Deissler, Dorothea Gadzicki, Andrea Gehrig, Karin Kast, Kerstin Rhiem, Alfons Meindl, Dieter Niederacher, Nina Ditsch, Hansjoerg Plendl, Sabine Preisler-Adams, Stefanie Engert, Christian Sutter, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Bernhard H F Weber, Brita Arver, Marie Stenmark-Askmalm, Niklas Loman, Richard Rosenquist, Zakaria Einbeigi, Katherine L Nathanson, Timothy R Rebbeck, Stephanie V Blank, David E Cohn, Gustavo C Rodriguez, Laurie Small, Michael Friedlander, Victoria L Bae-Jump, Anneliese Fink-Retter, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy-Kheng Tea, Noralane M Lindor, Bella Kaufman, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Anne-Marie Gerdes, Inge Sokilde Pedersen, Sanne Traasdahl Moeller, Torben A Kruse, Uffe Birk Jensen, Joseph Vijai, Kara Sarrel, Mark Robson, Noah Kauff, Anna Marie Mulligan, Gord Glendon, Hilmi Ozcelik, Bent Ejlertsen, Finn C Nielsen, Lars Jønson, Mette K Andersen, Yuan Chun Ding, Linda Steele, Lenka Foretova, Alex Teulé, Conxi Lazaro, Joan Brunet, Miquel Angel Pujana, Phuong L Mai, Jennifer T Loud, Christine Walsh, Jenny Lester, Sandra Orsulic, Steven A Narod, Josef Herzog, Sharon R Sand, Silvia Tognazzo, Simona Agata, Tibor Vaszko, Joellen Weaver, Alexandra V Stavropoulou, Saundra S Buys, Atocha Romero, Miguel de la Hoya, Kristiina Aittomäki, Taru A Muranen, Mercedes Duran, Wendy K Chung, Adriana Lasa, Cecilia M Dorfling, Alexander Miron, BCFR, Javier Benitez, Leigha Senter, Dezheng Huo, Salina B Chan, Anna P Sokolenko, Jocelyne Chiquette, Laima Tihomirova, Tara M Friebel, Bjarni A Agnarsson, Karen H Lu, Flavio Lejbkowicz, Paul A James, Per Hall, Alison M Dunning, Daniel Tessier, Julie Cunningham, Susan L Slager, Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S Pankratz, Kenneth Offit, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, and CIMBA

Subjects
Genetics, QH426-470
Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013
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5. DNA methylation biomarkers in peripheral blood of patients with head and neck squamous cell carcinomas. A systematic review.

Author

Christian Sander Danstrup, Mette Marcussen, Inge Søkilde Pedersen, Henrik Jacobsen, Karen Dybkær, and Michael Gaihede

Subjects
Medicine, Science
Abstract

BackgroundHead and neck squamous cell carcinomas (HNSCC) are often diagnosed in advanced stages. In search of new diagnostic tools, focus has shifted towards the biological properties of the HNSCC, and the number of different biomarkers under investigation is rapidly growing.ObjectivesThe objective was to review the current literature regarding aberrantly methylated DNA found in peripheral blood plasma or serum in patients with HNSCC and to evaluate the diagnostic accuracy of these changes.MethodsThe inclusion criteria were clinical studies involving patients with verified HNSCC that reported findings of aberrantly methylated DNA in peripheral blood serum or plasma. We systematically searched PubMed, OVID Embase and Cochrane Library. In addition to the search, we performed forward and backward chaining in references and Web of Science. The protocol was registered in PROSPERO: CRD42019135406. Two authors independently extracted data. The quality and the risk of bias of the included studies were assessed by the QUADAS-2 tool.ResultsA total of 1,743 studies were found eligible for screening, while ultimately seven studies were included. All studies were found to have methodological weaknesses, mainly concerning patient selection bias. The best individual marker of HNSCC was Septin 9 in plasma with a sensitivity of 57% and a specificity of 95%.ConclusionsNone of the aberrantly methylated genes found in the retrieved studies are applicable as single diagnostic markers for HNSCC and the best gene-panels still lack diagnostic accuracy. Future studies may benefit from newer sequencing techniques but validation studies with well-designed cohorts are also needed in the process of developing epigenetic based diagnostic tests for HNSCC.

Published
2020
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6. Hypermethylated DNA, a circulating biomarker for colorectal cancer detection.

Author

Simon Ladefoged Rasmussen, Henrik Bygum Krarup, Kåre Gotschalck Sunesen, Martin Berg Johansen, Mogens Tornby Stender, Inge Søkilde Pedersen, Poul Henning Madsen, and Ole Thorlacius-Ussing

Subjects
Medicine, Science
Abstract

Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection.We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC.None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5.Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.

Published
2017
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