Author: "Diana Eccles" / Publisher: american association for cancer research (aacr) - Searchworks@Jio Institute Digital Library Search Results

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1. Supplementary Grant Support from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Grant Support
Published: 2023
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2. Perspective on This Article from A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis

Author: John C. Mathers, Steffen Bülow, Robin K. S. Phillips, Julie Coaker, Hans F. A. Vasen, Gabriela Möslein, Eamonn R. Maher, Riccardo Fodde, D. Gareth Evans, Anthony Ellis, Diana Eccles, Malcolm G. Dunlop, Lucio Bertario, Faye Elliott, Pamela D. Chapman, D. Timothy Bishop, and John Burn
Abstract: Perspective on This Article from A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis
Published: 2023
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3. Supplementary Methods, Figures S1 - S3 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.
Published: 2023
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4. Supplementary Tables S1 - S10 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.
Published: 2023
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5. Supplementary Tables 1 - 4 from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

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

Author: Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
Published: 2023
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7. 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
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8. Supplementary Table 2 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.
Published: 2023
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9. Supplementary Table 1 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 1. The 3,248 SNPs included in the study
Published: 2023
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10. Data from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Purpose: Although most patients with estrogen receptor (ER)–positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.Experimental Design: We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy.Results: A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37–2.07; P = 6.34 × 10−7] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30–3.60; Pinteraction = 0.003) and HR = 7.77 (95% CI, 0.93–64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses.Conclusions: Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment. Clin Cancer Res; 21(18); 4086–96. ©2015 AACR.
Published: 2023
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11. Legends to Supplementary Figures S1 to S6 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Legends to Supplementary Figures S1 to S6. This document comprises the legends to the supplementary figures.
Published: 2023
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12. Supplementary Figure S5 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Figure S5. Regional plot using P-values derived from univariate Cox's regression model from HEBCS and POSH GWS meta-analysis and includes both imputed and the genotyped SNPs 250 kb either side of the rs8113308.
Published: 2023
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13. Supplementary Figures 1-5, Tables 1-8 from Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

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

Author: Georgia Chenevix-Trench, Penelope M. Webb, Anna deFazio, Ellen L. Goode, Paul D.P. Pharoah, Stuart MacGregor, Andrew Berchuck, Yoke-Eng Chiew, Catherine Kennedy, Thomas Sellers, Rosalind Glasspool, Nadeem Siddiqui, Karen Carty, James Paul, Ian McNeish, Lene Lundvall, Claus Høgdall, Yukie Bean, Tanja Pejovic, Irene Orlow, Elisa V. Bandera, Daniel W. Cramer, Kathryn L. Terry, Edwin S. Iversen, Joellen M. Schildkraut, Robert A. Vierkant, Julie M. Cunningham, Brooke L. Fridley, Susanne Kruger Kjaer, Allan Jensen, Estrid Høgdall, Zachary C. Fogarty, Melissa C. Larson, Madalene Earp, Stacey J. Winham, Sandra Orsulic, Jenny Lester, Christine Walsh, Beth Y. Karlan, Peter Hillemanns, Jacobus Pisterer, Philipp Harter, Ira Schwaab, Andreas du Bois, Florian Heitz, Pamela J. Thompson, Michael E. Carney, Lynne R. Wilkens, Marc T. Goodman, Beata Spiewankiewicz, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Celeste L. Pearce, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Simon A. Gayther, Argyrios Ziogas, Hoda Anton-Culver, Rebecca Sutphen, Joseph H. Rothstein, Valerie McGuire, Alice S. Whittemore, Weiva Sieh, Diana Eccles, Ian Campbell, Valerie Rhenius, Honglin Song, Nicolas Wentzensen, Jolanta Lissowska, Louise Brinton, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Douglas A. Levine, Kirsten B. Moysich, Roberta B. Ness, Francesmary Modugno, Jenny Chang-Claude, Jennifer A. Doherty, Mary Anne Rossing, Sandrina Lambrechts, Ignace Vergote, Els Van Nieuwenhuysen, Diether Lambrechts, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Peter A. Fasching, Bo Gao, Yi Lu, Jonathan Beesley, Siddhartha Kar, Jonathan P. Tyrer, and Sharon E. Johnatty
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3).Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.
Published: 2023
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15. Data from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author: Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block
Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.
Published: 2023
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16. Supplementary Table 3 from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Supplementary Table 3. Results of the statistical analyses of SNPs from project 12 in BRCA-mutation carriers affected or non-affected with breast cancer and according to their estrogen receptor status.
Published: 2023
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17. Supplementary Figure S1 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Figure S1. REMARK diagram describing work flow and sample selection in this study.
Published: 2023
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18. Supplementary Tables 1-9 from Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author: Antonis C. Antoniou, Douglas F. Easton, Georgia Chenevix-Trench, Beth Karlan, Christine Walsh, Jenny Gross, Kate Nathanson, Simon A. Gayther, Lara Sucheston, Kunle Odunsi, Mary Beattie, Robert Nussbaum, Susan L. Neuhausen, Linda Steele, Karin Henriksson, Anna von Wachenfeld, Johanna Rantala, Paolo Aretini, Maria Caligo, Torben Kruse, Anne-Marie Gerdes, Mads Thomassen, Kevin Sweet, Leigha Senter, Amanda Ewart Toland, Evgeny Imyanitov, Anna Sokolenko, Mark H. Greene, Phuong L. Mai, Christine Rappaport, Muy-Kheng Tea, Christian F. Singer, Mia M. Gaudet, Rita Sakr, Kenneth Offit, Csilla Szabo, Noralane M. Lindor, Vernon S. Pankratz, Zachary Fredericksen, Xianshu Wang, Judy E. Garber, Nadine Tung, Wendy Rubinstein, Timothy R. Rebbeck, Stephen Fox, Max Yan, Emma D'Andrea, Simona Agata, Marco Montagna, Jacques Simard, Martine Dumont, Rosa B. Barkardottir, Adalgeir Arason, Bjarni A. Agnarsson, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Kristiina Aittomäki, Päivi Heikkilä, Tuomas Heikkinen, Carmen Cañadas, Miguel de la Hoya, Trinidad Caldes, Beth N. Peshkin, Claudine Isaacs, Laure Barjhoux, Muriel Belotti, Dominique Stoppa-Lyonnet, Heidrun Gevensleben, Ines Schönbuchner, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Doroteha Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Norbert Arnold, Karin Kast, Alfons Meindl, Barbara Wappenschmidt, Rita K. Schmutzler, Andrew K. Godwin, JoEllen Weaver, Catherine Houghton, Lucy E. Side, Mark T. Rogers, Lisa Walker, Carole Brewer, D. Gareth Evans, Debra Frost, Susan Peock, Rob B. van der Luijt, Mieke Kriege, Frans B. Hogervorst, Muhammad U. Rashid, Ute Hamann, Paolo Radice, Laura Ottini, Anna Laura Putignano, Riccardo Dolcetti, Barbara Pasini, Sara Volorio, Monica Barile, Bernard Peissel, Siranoush Manoukian, Javier Benítez, Alexandra Stavropoulou, Ana Osorio, Finn C. Nielsen, Thomas V. O. Hansen, Laima Tihomirova, Ramunas Janavicius, Esther M. John, Frances O'Malley, David Goldgar, Mary Beth Terry, Melissa C. Southey, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Christoph Engel, Fergus J. Couch, Anna Marie Mulligan, Mark Sherman, Mark Robson, Amanda Spurdle, Susan J. Ramus, Heli Nevanlinna, Diana Eccles, Susan M. Domchek, Irene L. Andrulis, Daniel Barrowdale, and Nasim Mavaddat
Abstract: PDF file - 127K
Published: 2023
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19. Data from Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Eitan Friedman, Antonis C. Antoniou, Georgia Chenevix-Trench, Paul D.P. Pharoah, Andrew Lee, Sue Healey, Daniel Barrowdale, Lesley McGuffog, Karoline B. Kuchenbaecker, Åke Borg, Marie Stenmark Askmalm, Hans Ehrencrona, Anna von Wachenfeldt, Johanna Rantala, Yael Laitman, Uffe Birk Jensen, Mads Thomassen, Inge Sokilde Pedersen, Anders Bojesen, Amanda Ewart Toland, Irene L. Andrulis, Sandrine Tchatchou, Gord Glendon, Anna Marie Mulligan, Gad Rennert, Phuong L. Mai, Mark H. Greene, Catherine M. Phelan, Muy-Kheng M. Tea, Georg Pfeiler, Daphne Geschwantler Kaulich, Christine Rappaport, Christian F. Singer, Andreas Berger, Vijai Joseph, Liying Zhang, Mark E. Robson, Lauren Jacobs, Marina Corines, Kenneth Offit, Csilla I. Szabo, Xianshu Wang, Noralane M. Lindor, Fergus J. Couch, Curtis Olswold, Manuel R. Teixeira, Jocelyne Chiquette, Adalgeir Arason, Grzegorz Sukiennicki, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Cezary Cybulski, Lidia Feliubadalo, Joan Brunet, Conxi Lazaro, Ignacio Blanco, Orland Diez, Edith Olah, J. Margriet Collée, Helena C. van Doorn, Margreet G.E.M. Ausems, Nicoline Hoogerbrugge, Maaike P.G. Vreeswijk, Annemarie H. van der Hout, Hanne E.J. Meijers-Heijboer, Theo A.M. van Os, Kristiina Aittomäki, Heli Nevanlinna, Pedro Perez Segura, Miguel de la Hoya, Larry J. Copeland, Gustavo C. Rodriguez, Michael L. Friedlander, Marion Piedmonte, Muriel Belotti, Sylvie Mazoyer, Pascal Pujol, Olivier Caron, Olga M. Sinilnikova, Nadia Boutry-Kryza, Lisa Golmard, Laurence Venat-Bouvet, Laure Barjhoux, Isabelle Coupier, Francesca Damiola, Dominique Stoppa-Lyonnet, Claude Houdayer, Capucine Delnatte, Bruno Buecher, Brigitte Bressac-de Paillerets, Shan Wang-Gohrke, Barbara Wappenschmidt, Raymonda Varon-Mateeva, Norbert Arnold, Nina Ditsch, Kerstin Rhiem, Karin Kast, Hansjoerg Plendl, Doris Steinemann, Dieter Niederacher, Christoph Engel, Christian Sutter, Andrea Gehrig, Alfons Meindl, Tom Van Maerken, Kathleen Claes, Andrew K. Godwin, Trevor Cole, Steve Ellis, Shirley V. Hodgson, Rosemarie Davidson, Radka Platte, Patrick J. Morrison, Mary E. Porteous, Mark T. Rogers, M. John Kennedy, Lucy E. Side, Louise Izatt, Lisa Walker, Julian Barwell, Julian Adlard, Marc Tischkowitz, Jackie Cook, Angela Brady, Diana Eccles, Debra Frost, D. Gareth R. Evans, Claire Foo, Carole Brewer, Alan Donaldson, Judy E. Garber, Florentia Fostira, Athanassios Vratimos, Paolo Radice, Maria Grazia Tibiletti, Aline Martayan, Laura Papi, Giuseppe Giannini, Alessandra Viel, Stefano Fortuzzi, Frederique Mariette, Filomena Ficarazzi, Monica Barile, Giulietta Scuvera, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Jeffrey N. Weitzel, Kathleen R. Blazer, Edye E. Conway, Javier Benitez, Cristina Martínez-Bouzas, Ana Osorio, Lars Jønson, Bent Ejlertsen, Anne-Marie Gerdes, Thomas V.O. Hansen, Susan L. Neuhausen, Yuan Chun Ding, Elizabeth J. van Rensburg, Cecilia M. Dorfling, Ramunas Janavicius, Saundra S. Buys, David E. Goldgar, Melissa C. Southey, Alex Miron, Wendy K. Chung, Jenny Lester, Sandra Orsulic, Beth Y. Karlan, Banu K. Arun, Timothy R. Rebbeck, Susan M. Domchek, Katherine L. Nathanson, Robert L. Nussbaum, Olufunmilayo I. Olopade, Encarna B. Gómez Garcia, Anna Jakubowska, Jan Lubinski, Laura Matricardi, Marco Montagna, Ana-Teresa Maia, Felicity Lose, Logan C. Walker, Amanda B. Spurdle, Frederieke H. van der Baan, Marjanka K. Schmidt, Matti A. Rookus, Bowang Chen, Stefan Wilkening, Ute Hamann, Douglas F. Easton, Rosalind A. Eeles, Penny Soucy, Jacques Simard, Rita K. Schmutzler, Anja Rudolph, Kirsten B. Moysich, Jenny Chang-Claude, and Paolo Peterlongo
Abstract: Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.
Published: 2023
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20. Supplementary Tables 1 through 3 from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author: Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block
Abstract: PDF - 149K, Supplemental Table 1. Participating invasive epithelial ovarian cancer studies. Supplementary Table 2. NF-κB genes studied. Supplemental Table 3. Association between clinical variables and overall survival.
Published: 2023
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21. Supplementary Methods and Supplementary Tables S1-S6 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Methods and Supplementary Tables S1-S6. Supplementary Table S1. Univariate Cox's regression analysis within estrogen receptor positive patients receiving endocrine treatment with stage-1 meta-analysis fullfilling the P-value thresholds. Supplementary Table S2. Association for SNP rs8113308 with clinical and pathological features of the breast cancer tumors in a pooled set of HEBCS GWS, POSH GWS and POSH validation. Supplementary Table S3. Association for SNP rs4767413 with clinical and pathological features of the breast cancer tumors in a pooled set of HEBCS GWS, POSH GWS and POSH validation. Supplementary Table S4. Cis eQTL analysis. Expression in ER positive breast tumor and in ER negative breast tumor from METABRIC. Supplementary Table S5. Peripheral blood eQTL. Supplementary Table S6. Trans eQTL analysis. Expression in ER positive breast tumor and in ER negative breast tumor from METABRIC.
Published: 2023
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22. 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
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23. Supplementary Figure S6 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Figure S6. Protein-protein interaction network.
Published: 2023
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24. Supplementary Figure S3 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Figure S3. Kaplan-Meier plots of cumulative 10-year survival of rs8113308 genotypes in POSH validation dataset
Published: 2023
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25. Supplementary Figure S4 from Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Heli Nevanlinna, Diana Eccles, Carl Blomqvist, Jianjun Liu, Kristiina Aittomäki, William Tapper, Sajjad Rafiq, Rainer Fagerholm, and Sofia Khan
Abstract: Supplementary Figure S4. Forest plots of hazard ratios and their confidence intervals separately for studies HEBCS GWS and POSH GWS (stage-1) and POSH validation and SUCCESS-A (stage-2) along with the meta-analysis P-value of the stage-1 and stage-2.
Published: 2023
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26. Supplementary Figure 3 from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 53K, Regional plot of p-values arising from cox-proportional hazard models, 250 kb either side of the rs3785982 variant in stage-1. P-values are from imputed data alone.
Published: 2023
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27. Supplementary Figure 4 from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 52K, Regional plot of p-values arising from cox-proportional hazard models, 250 kb either side of the rs2774307 variant in stage-1. P-values are from imputed data alone.
Published: 2023
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28. Supplementary Figure 1 from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 36K, Principal Components of whole genome data from the POSH study. The plot shows first two principal component based on post quality control genome wide data.
Published: 2023
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29. 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
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30. 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
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31. Supplementary Figure Legend from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 45K
Published: 2023
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32. Supplementary Figure 2 from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 55K, Regional plot of p-values arising from cox-proportional hazard models, 250 kb either side of the rs3884558 variant in stage-1. P-values are from imputed data alone.
Published: 2023
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33. Supplementary Materials and Methods, Tables 1-5 from Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer

Author: Fergus J. Couch, Xianshu Wang, Heli Nevanlinna, Drakoulis Yannoukakos, Jenny Chang-Claude, Douglas F. Easton, Paul Pharoah, Ute Hamann, Gianluca Severi, Isabel dos Santos Silva, Diether Lambrechts, Grant W. Montgomery, Nicholas G. Martin, Arto Mannermaa, Sara Margolin, Sarah-Jane Dawson, Fiona M. Blows, Jianjun Liu, Astrid Irwanto, Carl Blomqvist, Dario Greco, Jonathan Beesley, Veli-Matti Kosma, Ian Tomlinson, Senno Verhoef, Laura Baglietto, Graham G. Giles, Olivia Fletcher, Julian Peto, Hilde Janssen, Erik Van Limbergen, Yon-Dschun Ko, Arja Jukkola-Vuorinen, Katri Pylkäs, Swati Kulkarni, Foluso Ademuyiwa, Thomas Dünnebier, Asta Försti, Thomas Rüdiger, JoEllen Weaver, Eric Ross, Harsh Pathak, Robert B. Diasio, Zachary Fredericksen, Janet E. Olson, Rosemary Balleine, Christine L. Clarke, George Fountzilas, Athanasios M. Dimopoulos, Dimitrios Pectasides, Florentia Fostira, Irene Konstantopoulou, Hans-Peter Sinn, Judith Heinz, Dieter Flesch-Janys, Stephan Nickels, Rebecca Hein, Nikki Graham, Lorraine Durcan, Susan M. Gerty, William J. Tapper, Arif B. Ekici, Rüdiger Schulz-Wendtland, Matthias W. Beckmann, Arndt Hartmann, Elinor Sawyer, Simon S. Cross, Angela Cox, Marjanka K. Schmidt, Hiltrud Brauch, Robert Winqvist, Christine Ambrosone, Andrew K. Godwin, Jane E. Carpenter, Diana Eccles, Penelope Miron, Peter A. Fasching, Curtis Olswold, Timothy Lesnick, Susan Slager, Adam M. Lee, Celine M. Vachon, and Kristen N. Stevens
Abstract: PDDF file - 167K
Published: 2023
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34. Supplementary Figure 5 from Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer

Author: Diana Eccles, Jianjun Liu, Heli Nevanlinna, Fergus J. Couch, Carl Blomqvist, Sue Gerty, Ioannis Politopoulos, Sofia Khan, Andrew Collins, William Tapper, and Sajjad Rafiq
Abstract: PDF file - 54K, Regional plot of p-values arising from cox-proportional hazard models, 250 kb either side of the rs1387389 variant in stage-1. P-values are from imputed data alone.
Published: 2023
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35. Abstract 3057: Second primary cancer risks for female and male breast cancer survivors

Author: Isaac Allen, Tameera Rahman, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Hend Hassan, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Beth Torr, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, and Antonis C. Antoniou
Subjects: Cancer Research, Oncology
Abstract: Background: Second primary cancer (SPC) incidence is rising among breast cancer (BC) survivors, but these risks remain unclear. We estimated SPC risks for male and female BC survivors using large-scale electronic health record data from a linkage of National Cancer Registration and Analysis Service data and Hospital Episode Statistics surgical records in England. Material and Methods: We used a retrospective cohort study design comprising 763,578 female and 4,795 male BC survivors first diagnosed with BC between 1995-2018. We calculated overall and site-specific SPC standardized incidence ratios (SIRs) by comparing observed and expected SPC counts for 19 cancer sites. Study participants were followed from one year after the first BC diagnosis until either a SPC diagnosis (excluding ipsilateral breast and non-melanoma skin cancers), death, migration, relevant surgical procedures, or the end of 2019. Expected SPC counts were calculated using year-, age- and sex-specific cancer incidence rates in the general English population. We stratified the SIRs by age group, sex, and cancer site. We estimated Kaplan-Meier absolute risks of site-specific SPCs and assessed the influence of age at first BC diagnosis using Cox proportional hazards models. Results: There were 68,550 and 720 incident SPCs among female and male BC survivors, respectively. There was a significant increased risk of all SPCs combined for female BC survivors (SIR: 1.19, 95%CI: 1.18-1.20). There were significant increased risks for SPC at all sites combined, all non-breast sites combined, and at 12 further specific sites for females and at 2 specific sites for males. Among females, the increase was greatest for contralateral breast (SIR: 1.82, 95%CI: 1.79-1.85) and uterine cancers (SIR: 1.80, 95%CI: 1.76-1.85). The risk at all sites combined was higher for women first diagnosed with BC before age 50 (SIR: 1.89, 95%CI: 1.85-1.92) compared to women diagnosed with BC at age 50 or over (SIR: 1.11, 95%CI: 1.10-1.12). The largest associations were observed for contralateral breast (SIR: 3.19, 95%CI: 3.11-3.29) and uterine (SIR: 1.77, 95%CI: 1.73-1.82) SPCs in the younger and older age groups, respectively. Increasing age at first female BC diagnosis was associated with decreasing CBC absolute risks, but significantly increased absolute risks of all other SPCs. Male BC survivors were at increased risk of contralateral breast (SIR: 42.39, 95%CI: 28.39-60.89) and prostate (SIR: 1.29, 95%CI: 1.13-1.46) SPCs. Conclusions: This is the largest study to date to assess SPC risks following BC in either men or women. SPC risks were significantly increased, both in combination and at specific sites. These findings could help guide clinical management, such as screening recommendations, for BC survivors. Further analysis is underway to investigate the effects of chemotherapy, radiotherapy, hormonal therapy, comorbidities, or germline BC susceptibility. Citation Format: Isaac Allen, Tameera Rahman, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Hend Hassan, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Beth Torr, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks for female and male breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3057.
Published: 2023
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36. Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Author: Usha Menon, Ralf Bützow, Siddhartha Kar, Jonathan Tyrer, Francesmary Modugno, Ellen L. Goode, Diana Eccles, Cristina Rodríguez-Antona, Renée T. Fortner, Linda E. Kelemen, Elio Riboli, Javier Benitez, Taymaa May, Kexin Chen, David G. Huntsman, Susana Banerjee, Penelope M. Webb, Rosalind Glasspool, Hoda Anton-Culver, Andrew Berchuck, Emily White, Thilo Dörk, Lang Wu, Douglas A. Levine, Heli Nevanlinna, Anita Koushik, Joe Dennis, Veronica Wendy Setiawan, Walter C. Willett, Yingchang Lu, Håkan Olsson, Nicolas Wentzensen, Kang Shan, Holly R. Harris, N. Charlotte Onland-Moret, Claus Høgdall, Jennifer A. Doherty, Fei Ye, Yaohua Yang, Qiuyin Cai, Linda S. Cook, Jacek Gronwald, Keitaro Matsuo, Joellen M. Schildkraut, James D. Brenton, Isabelle Romieu, Shelley S. Tworoger, Anna H. Wu, Alvaro N.A. Monteiro, Roberta B. Ness, Paul D.P. Pharoah, James Paul, Alicia Beeghly-Fadiel, Wei Zheng, Lambertus A. Kiemeney, Rebecca Sutphen, Thomas A. Sellers, Michelle A.T. Hildebrandt, Yin Ling Woo, Simon A. Gayther, Meir J. Stampfer, Diether Lambrechts, Marc T. Goodman, Weiva Sieh, Line Bjørge, Lukasz Szafron, Leon F.A.G. Massuger, Daniel W. Cramer, Bingshan Li, Susan J. Ramus, Nadeem Siddiqui, Dale P. Sandler, Jirong Long, Peter A. Fasching, Tanja Pejovic, Drakoulis Yannoukakos, Florian Heitz, Beth Y. Karlan, Estrid Høgdall, Malcolm C. Pike, Anthony J. Swerdlow, Georgia Chenevix-Trench, Catherine M. Phelan, Xiang Shu, Digna R. Velez Edwards, Celeste Leigh Pearce, Sue K. Park, Patricia G. Moorman, Soo-Hwang Teo, Nhu D. Le, Susanne K. Kjaer, Kirsten B. Moysich, Graham G. Giles, Alicja Wolk, Iain A. McNeish, Xiao-Ou Shu, Jenny Chang-Claude, L Yan, Anna deFazio, Ian G. Campbell, HUSLAB, Department of Pathology, Medicum, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum
Subjects: 0301 basic medicine, Cancer Research, endocrine system diseases, Medizin, PROTEIN, Genome-wide association study, Carcinoma, Ovarian Epithelial, VARIANTS, THERAPY, DISEASE, Cohort Studies, Models, Ovarian Epithelial, MAPT, WIDE ASSOCIATION, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cancer, Ovarian Neoplasms, Regulation of gene expression, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Tumor, Methylation, female genital diseases and pregnancy complications, Ovarian Cancer, 3. Good health, Oncology, CpG site, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], DNA methylation, Female, Life Sciences & Biomedicine, Risk, SUSCEPTIBILITY LOCI, 3122 Cancers, Oncology and Carcinogenesis, Biology, Article, White People, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Rare Diseases, Genetic, Predictive Value of Tests, Clinical Research, Genetic model, Biomarkers, Tumor, Genetics, medicine, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Epigenetics, Science & Technology, Models, Genetic, IDENTIFICATION, Prevention, Carcinoma, Human Genome, DNA Methylation, medicine.disease, 030104 developmental biology, TISSUE, Cancer research, Women's Health, 1112 Oncology And Carcinogenesis, Biomarkers
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Published: 2019
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37. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Ellen L. Goode, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Joe Dennis, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Rosalind Glasspool, Diana Eccles, Susanne K. Kjaer, Roberta B. Ness, James Paul, Matthias Dürst, Camilla Krakstad, Irene Orlow, Rachel Palmieri Weber, Jonathan Tyrer, Valerie McGuire, Matthias W. Beckmann, Thomas A. Sellers, Elizabeth M. Poole, Ian G. Campbell, Arif B. Ekici, Steven A. Narod, Lotte Nedergaard, Shan Wang-Gohrke, Estrid Høgdall, Yurii B. Shvetsov, Douglas F. Easton, Sandrina Lambrechts, Linda E. Kelemen, Zhihua Chen, Karen Lu, Elisa V. Bandera, Qiyuan Li, Joellen M. Schildkraut, Agnieszka Dansonka-Mieszkowska, Liisa M. Pelttari, Kate Lawrenson, Sandra Orsulic, Ed Dicks, Kirsten B. Moysich, Melissa C. Southey, Christine Walsh, Louise A. Brinton, Argyrios Ziogas, Yukie Bean, Julie M. Cunningham, Patricia Harrington, Philipp Harter, Sara H. Olson, Keitaro Matsuo, Alvaro N.A. Monteiro, Claus Høgdall, Anne M. van Altena, Jenny Lester, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Yu-Tang Gao, Shelley S. Tworoger, Maria Bisogna, Michelle A.T. Hildebrandt, Yian Ann Chen, Iain A. McNeish, Allan Jensen, Diether Lambrechts, Usha Menon, Satoyo Hosono, Pamela J. Thompson, Yin Ling Woo, Jennifer Permuth-Wey, Francesmary Modugno, Matthew L. Freedman, Linda S. Cook, Harvey A. Risch, Ya-Yu Tsai, Marc T. Goodman, Dong Liang, Kathryn L. Terry, Soo Hwang Teo, Lara E. Sucheston-Campbell, Ira Schwaab, Robert A. Vierkant, Georgia Chenevix-Trench, Ralf Bützow, Siddhartha Kar, Wei Zheng, Nhu D. Le, Andrew Berchuck, Brooke L. Fridley, Edwin S. Iversen, Robert P. Edwards, Peter Hillemanns, Daniel W. Cramer, Mary Anne Rossing, Thilo Dörk, Malcolm C. Pike, Jolanta Kupryjanczyk, Anja Rudolph, Joseph H. Rothstein, Douglas A. Levine, Xiao-Ou Shu, Nicolas Wentzensen, Hannah P. Yang, Graham G. Giles, Hoda Anton-Culver, Line Bjørge, Peter A. Fasching, Catherine M. Phelan, Simon A. Gayther, Ignace Vergote, Alexander Hein, Cezary Cybulski, Ingvild L. Tangen, Els Van Nieuwenhuysen, Joseph L. Kelley, Honglin Song, Helen Baker, Alice S. Whittemore, Melissa Kellar, Kunle Odunsi, Bu Tian Ji, Heli Nevanlinna, Jolanta Lissowska, Shashi Lele, Barry P. Rosen, Katja K.H. Aben, Karen Carty, Leon F.A.G. Massuger, Iwona K. Rzepecka, Susan J. Ramus, Angela Brooks-Wilson, Xifeng Wu, Ingo B. Runnebaum, Lene Lundvall, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Jan Lubinski, Agnieszka Timorek, Nadeem Siddiqui, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Florian Heitz, Beth Y. Karlan, and Jacek Grownwald
Subjects: endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2015
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38. Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author: Jianjun Liu, William J. Tapper, Diana Eccles, Kristiina Aittomäki, Sajjad Rafiq, Carl Blomqvist, Heli Nevanlinna, Sofia Khan, and Rainer Fagerholm
Subjects: Oncology, Cancer Research, Estrogen receptor, Kaplan-Meier Estimate, 0302 clinical medicine, Medicine, Prospective Studies, Prospective cohort study, Aged, 80 and over, 0303 health sciences, Homozygote, Hazard ratio, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Antineoplastic Agents, Hormonal, Genotype, Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Breast cancer, Internal medicine, Humans, SNP, Endocrine system, Allele, Alleles, Aged, Proportional Hazards Models, 030304 developmental biology, Gynecology, business.industry, medicine.disease, Confidence interval, Multivariate Analysis, business, Chromosomes, Human, Pair 19, Genome-Wide Association Study
Abstract: Purpose: Although most patients with estrogen receptor (ER)–positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies. Experimental Design: We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy. Results: A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37–2.07; P = 6.34 × 10−7] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30–3.60; Pinteraction = 0.003) and HR = 7.77 (95% CI, 0.93–64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses. Conclusions: Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment. Clin Cancer Res; 21(18); 4086–96. ©2015 AACR.
Published: 2015
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39. Abstract P4-12-03: Triple-negative breast cancer: Frequency of inherited mutations in breast cancer susceptibility genes

Author: Celine M. Vachon, Peter A. Fasching, Angela Cox, Heli Nevanlinna, Judy Garber, Susan L. Slager, Vernon S. Pankratz, Penelope Miron, Curtis Olswold, Lucia Guidugli, Diana Eccles, Amanda E. Toland, Fergus J. Couch, Matthias W. Beckmann, Seth W. Slettedahl, Liisa M. Pelttari, Drakoulis Yannoukakos, Song Yao, Steven N. Hart, Brigitte Rack, Florentia Fostira, Hiltrud Brauch, Janet E. Olson, Christine B. Ambrosone, Andrew K. Godwin, Priyanka Sharma, George Fountzilas, Irene Konstantopoulou, and Arif B. Ekici
Subjects: Oncology, Genetics, Cancer Research, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, 3. Good health, Germline mutation, Breast cancer, Internal medicine, medicine, Family history, Allele, Ovarian cancer, business, Triple-negative breast cancer, Genetic testing
Abstract: Background: Guidelines recommend germline mutation testing of breast cancer predisposition genes in triple negative (TN) breast cancer cases with a family history of breast or ovarian cancer or when diagnosed under age 60. However, the prevalence of mutations in these genes among TN cases unselected for family history of breast or ovarian cancer is not known. Methods: To assess the frequency of mutations in 16 predisposition genes in TN cases we screened a large cohort of TN patients (n=1824) unselected for family history of breast or ovarian cancer from 12 centers and 824 study matched unaffected controls for mutations using a panel-based sequencing approach. Results: Deleterious mutations were identified in 15% of TN patients: 8.5% had BRCA1, 2.7% had BRCA2, and 3.6% had mutations in 12 other genes. Mutations in non-BRCA1/2 genes encoding proteins implicated in homologous recombination repair of DNA double strand breaks were detected at the same frequency as in breast cancer families. TN cases with mutations had high-grade tumors and were diagnosed at an earlier age than non-mutated cases. However, 10% of TN cases diagnosed at ≥60 years and 5% with no family history of cancer were also found to carry mutations. Inactivating mutations in non-BRCA1/2 predisposition genes were associated with moderate to high risks of TN breast cancer. Conclusions: National Comprehensive Cancer Network (NCCN) guidelines support clinical genetic testing of breast cancer predisposition genes in 95% of TN breast cancer patients carrying mutations in susceptibility genes. In contrast, National Institute of Health and Care Excellence (NICE) guidelines in the U.K. do not support genetic testing of a substantial proportion of TN patients with predisposing alleles. Frequency tables for inherited mutations in known predisposition genes based on age of diagnosis and family history of cancer will allow for selection of TN patients most likely to carry mutations in the predisposition genes. Citation Format: Fergus J Couch, Steven N Hart, Priyanka Sharma, Amanda Ewart Toland, Penelope Miron, Janet E Olson, Andrew Godwin, Vernon S Pankratz, Curtis Olswold, Seth Slettedahl, Lucia Guidugli, Matthias W Beckmann, Brigitte Rack, Arif B Ekici, Irene Konstantopoulou, Florentia Fostira, George Fountzilas, Liisa M Pelttari, Song Yao, Judy Garber, Angela Cox, Hiltrud Brauch, Christine Ambrosone, Heli Nevanlinna, Drakoulis Yannoukakos, Susan L Slager, Celine M Vachon, Diana M Eccles, Peter A Fasching. Triple-negative breast cancer: Frequency of inherited mutations in breast cancer susceptibility genes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-03.
Published: 2015
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40. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: Weiva Sieh, Anna H. Wu, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, David Van Den Berg, Joellen M. Schildkraut, Kimberly R. Kalli, Gottfried E. Konecny, Argyrios Ziogas, Usha Menon, Montserrat Garcia-Closas, Anja Rudolph, Jonathan Tyrer, Ann L. Oberg, Alice S. Whittemore, Brooke L. Fridley, Kunle Odunsi, Mary Anne Rossing, Beata Spiewankiewicz, Douglas A. Levine, Jennifer A. Doherty, Peter A. Fasching, Janusz Menkiszak, Matthew J. Maurer, Claus Høgdall, Zachary C. Fogarty, Louise A. Brinton, Galina Lurie, Diether Lambrechts, Allison F. Vitonis, Keith L. Knutson, Diana Eccles, Agnieszka Dansonka-Mieszkowska, Marc T. Goodman, Jenny Lester, Jolanta Kupryjanczyk, Nicolas Wentzensen, Celeste Leigh Pearce, Howard C. Shen, Simon A. Gayther, Kathryn L. Terry, Ira Schwaab, Bridget Charbonneau, Claudia C. Preston, Jan Lubinski, Krista M. Goergen, Georgia Chenevix-Trench, Susanne K. Kjaer, Irene Orlow, Sara H. Olson, Stanley B. Kaye, Matthias W. Beckmann, Daniel W. Cramer, Kate Lawrenson, Matthew S. Block, Paul D.P. Pharoah, Robert A. Vierkant, Chen Wang, Yukie Bean, Laura E. Hays, Sandrina Lambrechts, Catherine M. Phelan, Hoda Anton Culver, Kirsten B. Moysich, Estrid Høgdall, Malcolm C. Pike, Iwona K. Rzepecka, Ignace Vergote, Lara Sucheston, Joseph H. Rothstein, David N. Rider, Christine Walsh, Starr M. Ramirez, Evelyn Despierre, Lene Lundvall, Arif B. Ekici, Cezary Cybulski, Valerie McGuire, Anna deFazio, Ian G. Campbell, Hannah P. Yang, Alexander Hein, Roberta B. Ness, James Paul, Elisa V. Bandera, Jacek Gronwald, Andrew Berchuck, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Lisa E. Paddock, Lynn C. Hartmann, Sharon E. Johnatty, Philipp Harter, James M. Flanagan, Brenda Diergaarde, Julie M. Cunningham, Robert S. Brown, Allan Jensen, Thomas A. Sellers, Honglin Song, Susan J. Ramus, and Petra Seibold
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Immunology, Gene Expression, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, T-Lymphocytes, Regulatory, Article, Internal medicine, Genotype, medicine, Carcinoma, Humans, Mucinous carcinoma, Genetic Predisposition to Disease, Neoplasm Invasiveness, Germ-Line Mutation, Ovarian Neoplasms, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, Genetic Variation, FOXP3, Prognosis, medicine.disease, Patient Outcome Assessment, Clear cell carcinoma, Female, Neoplasm Grading, Ovarian cancer, Clear cell
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
Published: 2014
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41. Abstract P4-15-01: Integrin avb6 is a therapeutic target for high-risk breast cancer and enhances trastuzumab efficacy

Author: Jane Warwick, P Quinlan, William J. Tapper, Diana Eccles, Lee B. Jordan, P Chou, C Gillet, Antonio Saha, Shelia M. Violette, Jane Kendrew, AM Thompson, Stephen W. Duffy, R L Bowen, Andrew R. Green, Simon T. Barry, A Brentall, Rhian Gabe, Ian O. Ellis, Kate Moore, John Marshall, Ian R. Hart, S. Vallath, Kellie Brouilette, Gareth J. Thomas, JL Jones, Claude Chelala, Syed Haider, and Paul H. Weinreb
Subjects: Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, Integrin, Cancer, Disease, medicine.disease, Breast cancer, In vivo, Trastuzumab, Internal medicine, Cancer cell, Immunology, medicine, biology.protein, Antibody, skin and connective tissue diseases, business, medicine.drug
Abstract: The integrin avβ6 promotes migration, invasion and survival of cancer cells, but the biological relevance has yet to be ascertained in breast cancer. Our immunhistochemical analysis of over 2000 breast cancers has revealed that high expression of the protein for the integrin subunit beta6 (β6) is associated with very poor survival (HR = 1.99, P = 2.9×10-6) and increased metastases to distant sites (P = 0·02). This correlation was confirmed at the mRNA level via bioinformatic analysis of the 2000 women in the METABRIC cohort. Furthermore, co-expression of HER2 gave a significantly worse prognosis (HR = 3.43, P = 4×10-12), which we investigated further. We report from in vitro studies that HER2-driven invasion is mediated by αvβ6 in an Akt2-dependent manner. Using the well-tolerated αvβ6-blocking antibody 264RAD in vivo we show that antibody-blockade of this integrin suppressed growth of BT-474 and MCF-7/HER2-18 human breast cancer xenografts similarly to trastuzumab alone (P 264RAD or trastuzumab prolonged survival to a similar degree (14.3% and 33.33% treated mice alive after 100d, respectively, no significant difference) but again, when both drugs were combined 85.7% of mice were alive after 100d, a highly significant response compared with PBS (P Since 70% of women treated with trastuzumab either have, or develop resistance, we suggest combined targeting of αvβ6 and HER2 could provide an important novel therapy for thousands of women with breast cancer. In fact, over 39,000 American women annually (NIH statistics) will develop HER2+ breast cancers for which no specific therapies exist. Our data shows that in excess of 40% of these women with trastuzumab-resistant disease are also likely to express high levels of αvβ6. Our data also suggest that routine determination of the level of expression of αvβ6 on breast cancers would be a valuable clinical tool as it identifies novel high-risk groups of women that require enhanced therapeutic intervention. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-01.
Published: 2013
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42. Abstract P2-12-01: BRCA1 and BRCA2 in multifocal cancers: Results from the POSH study

Author: Diana Eccles, Bryony Eccles, Tom Maishman, Louise Stanton, and Ellen Copson
Subjects: Gynecology, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, Breast cancer, Internal medicine, Cohort, medicine, Genetic predisposition, Cancer Family, Family history, skin and connective tissue diseases, Ovarian cancer, business, Genetic testing
Abstract: Background: Multifocal (MF) breast cancers are more common in pre and perimenopausal women and in estrogen receptor (ER) positive disease. Young onset breast cancer and a positive family history of breast/ovarian cancer are characteristic of BRCA1 and BRCA2 carriers, but tumour receptor status and other pathological features may also be helpful in identifying BRCA gene carriers, particularly where family history is negative or unknown. Multifocal cancer may either be clonal in origin or unrelated multiple primaries (multicentric) and in a patient with a strong genetic predisposition the latter might be expected due to a field change effect. There are few data on whether multifocality is a predictor of an underlying BRCA 1 or BRCA2 mutation. A mutation frequency of 18% (combined BRCA1 and 2) in 61 multifocal cancers has been previously reported. We sought evidence of an association between multifocality and BRCA carrier status in young women both with and without a relevant cancer family history. Methods: POSH, the UK population based cohort study recruited breast cancer patients aged ≤40 at diagnosis. Family history data were collected by patient questionnaire (positive family history defined as any number of first or second degree relatives diagnosed with breast or ovarian cancer). Genetic testing occurred either as part of clinical breast cancer management or the research study. Results: MF cancer was present in 797 of 2956 patients (27.0%) of the whole POSH cohort, more frequent in ER positive (34.9%) than ER negative (19.9%) cancers (p Type of BRCA mutation with distribution of breast cancer by ER status Localised n = 150Multifocal n = 47Missing n = 17Total n = 214BRCA1110 (73.3%)17 (36.2%)9136 (63.6%)ER pos23 (20.9%)6 (35.3%)029 (21.3%)ER neg87 (79.1%)11 (64.7%)9107 (78.7%)BRCA240 (26.7%)30 (68.8%)878 (36.4%)ER pos33 (82.5%)27 (90.0%)666 (84.6%)ER neg7 (17.5%)3 (10.0%)212 (15.4%) Conclusions: Multifocal disease is associated with an increased probability of BRCA2 mutations in our data and may be an indicator of BRCA2 genetic status. The ratio of multifocal to unifocal disease in BRCA1, BRCA2 carriers and non BRCA1/2 cases was highest in BRCA2 cases for both ER positive and ER negative tumours. With the caveat of small numbers and incomplete testing of the cohort, there is some evidence pointing to BRCA2 causing a field effect rather than just as a function of predominantly ER positive cancers, and this characteristic may be useful in an algorithm to predict BRCA2 status incorporating further adjustment for other potential confounders. We plan to conduct further genetic testing across the whole cohort to refine the algorithm and to confirm the observed multifocal/BRCA2 association. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-01.
Published: 2013
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43. Abstract P1-09-05: The RAZOR trial: a phase II prevention trial of screening plus goserilin and raloxifene versus screening alone in pre-menopausal women at increased risk of breast cancer

Author: Diana Eccles, A Howell, Linda Ashcroft, Jenny Affen, Gareth Evans, Rosalind A. Eeles, Jack Cuzick, C Boggis, Jamie C. Sergeant, J Adams, J Motion, Rosemary Greenhalgh, J Hickman, Sara Bundred, Lesley Fallowfield, and Mitchell Dowsett
Subjects: Gynecology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Goserelin, Oophorectomy, Cancer, medicine.disease, Breast cancer, Oncology, Quality of life, Median follow-up, Internal medicine, medicine, Anxiety, Raloxifene, medicine.symptom, business, medicine.drug
Abstract: Background: Observational studies indicate that oophorectomy at about age 40 reduces breast cancer risk by approximately a half in high risk women. Widespread use of risk reducing oophorectomy is unlikely to be acceptable to these women. We explored the feasibility of giving goserelin to produce reversible ovarian suppression together with raloxifene to maintain bone mineral density (BMD). Objectives: The primary study objective was adherence to treatment. Secondary objectives were uptake of randomisation, side effects/quality of life and measures of effect on bone and in serum. Methods: Recruitment was from 3 UK Family History Clinics. Consenting women at ≥ 1 in 3 lifetime risk of breast cancer were randomised to control or monthly subcutaneous goserelin 3.6 mg and raloxifene 60 mg/d orally for two years. Questionnaires (Endocrine Symptom Checklist, Trait & State Anxiety, Sexual Activity & Cancer Worry) measuring toxicity/quality of life were administered by nurses. Dual energy X-ray absorptiometry (DXA) BMD measurements were performed in the treatment arm annually. Lipids and collagen breakdown products were measured by standard methods. Results: 75 of 511 (14.7%) women approached agreed to randomisation (38 to treatment and 37 to control). The major reason for non-entry was fear of side effects (85%). Median age was 37 and 35 years, for the experimental (A) and control arm (B), respectively. Median follow up is 8.8 years. 20/38 in arm A and 27/37 of controls completed the 24 m study. 18/38 women in arm A withdrew (13 [34%] because of side effects) and 10/37 in arm B for various reasons including the desire for risk reducing surgery (n = 4). No significant differences were seen in the Endocrine Symptom Sub-scale, State or Trait anxiety or Cancer Worry. However, Hot flushes, night and cold sweats (together p Conclusions: Uptake and adherence to treatment was relatively low in this group of women at high risk. The major reason for low uptake was fear of side effects and these were the major reason for drop out from treatment. Raloxifene did not maintain BMD. This approach to breast cancer prevention induced significant symptoms and bone loss, thus methods to ameliorate these need to be developed if ovarian suppression is to play a role in breast cancer prevention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-05.
Published: 2012
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44. Abstract S2-03: Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH)

Author: S Gerty, Brennan Decker, Tom Maishman, Diana Eccles, P D Simmonds, Doug Easton, Alison M. Dunning, Louise Stanton, William J. Tapper, Craig Luccarini, Ellen Copson, Ramsey I. Cutress, Douglas G. Altman, Jamie Allen, and Lorraine Durcan
Subjects: Gynecology, Oncology, Cancer Research, medicine.medical_specialty, Anthracycline, business.industry, Cancer, Retrospective cohort study, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, Cohort, medicine, 030212 general & internal medicine, Family history, skin and connective tissue diseases, business, Prospective cohort study, Cohort study
Abstract: Background Germline mutations in BRCA1/2 account for ∼3% of breast cancer cases but >10% of young patients who present with triple negative (TN) breast cancer. Young age at diagnosis is also associated with an increased risk of recurrence and inferior survival compared to older patients. Numerous publications describe an increased incidence of adverse biological features in tumours from young breast cancer patients; however it is unclear whether these fully explain the poor outcome. The effect of carrying a BRCA1/2 mutation on the prognosis of breast cancer remains controversial with retrospective studies reporting better, similar and worse outcomes for mutation carriers compared to patients with sporadic tumours. BRCA carriers could feasibly have enhanced or reduced sensitivity to certain chemotherapeutics; however retrospective studies are problematic due to missing data and biased ascertainment. POSH is multicentre prospective observational cohort study designed to investigate factors which affect prognosis in young breast cancer patients (Copson et al, JNCI, 2013). Here we report the pathology, treatment and outcome of patients with TN tumours as a preliminary analysis to determine the impact of a germline BRCA1 mutation on survival. The whole cohort analysis including BRCA1 and BRCA2 is in progress. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 127 UK oncology centres between 2000 and 2008. Patient characteristics, family history, risk factors, tumour pathology and treatment information, and blood DNA were collected at recruitment. Follow-up data were collected at 6 and 12 months, then annually. Summary statistics were used to describe patients by BRCA1 status. Kaplan-Meier estimates were used to describe univariate survival data. Results BRCA1 status is currently available for 542 patients with TN tumours. Pathogenic BRCA1 mutations were identified in 122 patients (BRCA1+); 420 had no BRCA1 mutation (BRCA1-). BRCA1+ were younger than BRCA1- (median age 34 vs 36 years, p Median follow-up was 7.3 years. Overall survival of patients with stage 1-3 disease treated with anthracycline +/- taxane neoadjuvant chemotherapy (n=538; 151 deaths) was better for BRCA1+ vs BRCA1- (79.1% vs 73.6% at 5-yrs; HR[95%CI]=0.84[0.57,1.25],p=0.388). Distant disease-free survival (DDFS) was also higher for BRCA1+ (5-yr DDFS 76.1% vs 71.5%; HR[CI]=0.92[0.63,1.35], p=0.682). Moreover, survival after first distant relapse was better for BRCA1+ patients (41.9% vs 36.8% at 1-yr; HR[CI]=0.78[0.51,1.18], p=0.233). Conclusions Our prospective data show better survival in young BRCA1+ patients with early TN breast cancer treated with anthracycline/-taxane chemotherapy than BRCA1- patients. However, the difference between the groups was not significant in this partial sample. Results for the whole cohort will be available by the time of the meeting. Citation Format: Eccles DM, Copson ER, Maishman T, Tapper W, Cutress R, Gerty S, Stanton L, Altman DG, Durcan L, Simmonds P, Decker B, Allen J, Luccarini C, Easton D, Dunning A, POSH Steering Group and Collaborators. Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-03.
Published: 2017
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45. P2-12-03: A Prospective Study of the Prognostic Implications of Being a BRCA1 Carrier for Young Onset Breast Cancer Patients

Author: P D Simmonds, Diana Eccles, S Gerty, L Dent, Lorraine Durcan, Ellen Copson, D Ward, and Douglas G. Altman
Subjects: Oncology, Gynecology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Retrospective cohort study, medicine.disease, Breast cancer, Median follow-up, Internal medicine, medicine, Family history, business, Prospective cohort study, Triple-negative breast cancer, Survival analysis
Abstract: Background BRCA1 gene carriers frequently develop triple negative breast cancer (TNBC) at young ages. Retrospective studies have reached conflicting conclusions about the prognostic implications of breast cancer diagnosed on a background of a constitutional BRCA1 gene mutation. Many studies have the disadvantages of retrospective design and small numbers or both. The Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) recruited 3024 patients diagnosed before 41 years of age and treated for breast cancer in the UK between 2000 and 2007 (protocol published: Eccles et al BMC Cancer 2008). Aim: To investigate the effect of family history and BRCA1 gene mutation status on breast cancer survival in women aged younger than 41 years at diagnosis. Methods: Cases in which the primary tumour pathology report was not available (2.8% of total) were excluded from this analysis. A completed family history questionnaire was available for 2907 cases (99% of total). The primary end point for this analysis was the development of distant metastases from breast cancer. All patients were younger than the starting age for screening in the UK except for known gene carriers of which there were only 8 in total, the remainder of identified gene carriers were tested after cancer diagnosis or as part of this study. Over 90% of patients received adjuvant or neoadjuvant chemotherapy with over 90% of these receiving an anthracycline based regimen. Kaplan Meier survival analysis and log rank test were used to assess survival differences. Results: 2937 patients were included in the analysis. Mean and median age at diagnosis was 36 years and the cohort was followed prospectively for a mean and median follow up time of 50 months. Overall distant disease free survival in the whole cohort was only 75% at 5 years. The effect of family history on presentation was explored. Patients who reported a first or second degree relative with breast cancer presented with smaller tumours (20mm compared to 22.5mm, p= 0.006) but no difference in axillary nodal status (p=0.2605). Survival was however significantly better comparing the 499 patients who reported a family history of breast cancer compared with the rest of the cohort (p=0.0164). 539 patients had been tested for mutations in the BRCA1/2 genes and 176 high risk gene BRCA1/BRCA2 carriers were identified. We compared 118 patients with a known BRCA1 gene mutation (almost all diagnosed after the cancer) to the 465 patients with confirmed TNBC (p=0.0118). Survival was significantly better in the BRCA1 carriers (p=0.0118). After excluding 29 gene carriers whose primary tumour showed any of ER, HER2 or PR as positive, the same improved survival trend was seen although significant at the 10% level (p=0.07). Conclusion: This prospective study indicates that BRCA1 gene carriers clearly do not have a worse prognosis when compared to triple negative breast cancers or young onset breast cancer overall and these early follow up data indicate an improved outlook in gene carriers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-03.
Published: 2011
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46. Late Toxicity Is Not Increased in BRCA1/BRCA2 Mutation Carriers Undergoing Breast Radiotherapy in the United Kingdom

Author: Douglas F. Easton, Anthony Howell, Audrey Ardern-Jones, Andrew Tutt, Roger A'Hern, Susan Shanley, Sue Ashley, Kate M. McReynolds, Susan C Short, D. Gareth Evans, Gerald Gui, Andrew D Baildam, Elizabeth Bancroft, Rosalind A. Eeles, John Yarnold, G.T. Royle, Linda Ashcroft, Indrajit Fernando, Lester Barr, Lori J. Pierce, Diana Eccles, and Shirley Hodgson
Subjects: Adult, Oncology, Heterozygote, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Genes, BRCA2, Mammary gland, Genes, BRCA1, Breast Neoplasms, Pericarditis, Breast cancer, Internal medicine, medicine, Humans, skin and connective tissue diseases, Telangiectasia, Germ-Line Mutation, Aged, Neoplasm Staging, Retrospective Studies, Cancer staging, Radiotherapy, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, United Kingdom, Surgery, Radiation therapy, Treatment Outcome, medicine.anatomical_structure, Case-Control Studies, Toxicity, Female, medicine.symptom, business, Follow-Up Studies
Abstract: Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. Results: No increase in clinically significant late toxicity was seen in the mutation carriers. Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.
Published: 2006
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47. Acute Chemotherapy–Related Toxicity Is Not Increased in BRCA1 and BRCA2 Mutation Carriers Treated for Breast Cancer in the United Kingdom

Author: Douglas F. Easton, Andrew D Baildam, Elizabeth Bancroft, Linda Ashcroft, Andrew Tutt, Kate M. McReynolds, Indrajit Fernando, Rosalind A. Eeles, Audrey Ardern-Jones, Susan Shanley, G.T. Royle, Lori J. Pierce, Sue Ashley, Diana Eccles, Shirley Hodgson, Gerald Gui, Ian E. Smith, Anthony Howell, D. Gareth Evans, Susan C Short, Roger A'Hern, John Yarnold, and Lester Barr
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Cyclophosphamide, Anthracycline, medicine.medical_treatment, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Neutropenia, Breast cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, skin and connective tissue diseases, Germ-Line Mutation, Aged, Neoplasm Staging, Retrospective Studies, Chemotherapy, Dose-Response Relationship, Drug, Radiotherapy, business.industry, Middle Aged, medicine.disease, United Kingdom, Acute toxicity, Treatment Outcome, Case-Control Studies, Toxicity, Immunology, Female, business, Follow-Up Studies, medicine.drug, Epirubicin
Abstract: Purpose: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003. Experimental Design: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers. Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02). Conclusions: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.
Published: 2006
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48. Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage

Author: Imogen Locke, Richard D. Williams, Zsofia Kote-Jarai, Susan Shanley, D. Gareth Evans, Mark Girolami, Ros Eeles, Francois Moreews, Diana Eccles, Ana Osorio, Ian Giddings, Lucy Matthews, and Colin Campbell
Subjects: Adult, Heterozygote, Cancer Research, Genotype, endocrine system diseases, DNA damage, Breast Neoplasms, Biology, Predictive Value of Tests, Gene expression, Cluster Analysis, Humans, skin and connective tissue diseases, Gene, Oligonucleotide Array Sequence Analysis, BRCA2 Protein, BRCA1 Protein, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Middle Aged, Molecular biology, BRCA2 Mutation Carrier, Gene expression profiling, Oncology, Mutation, Gene chip analysis, Female, DNA microarray, Apoptosis Regulatory Proteins, Software, DNA Damage
Abstract: Purpose: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. Experimental Design: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. Results: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. Conclusions: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.
Published: 2006
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49. Mammographic Density and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Fiona Douglas, Douglas F. Easton, Ros Eeles, Trevor Cole, Russell Davies, Judith Brown, Susan Peock, Iqbal Warsi, Diana Eccles, Shirley Hodgson, Louise Izatt, Margaret Cook, Antonis C. Antoniou, Joan Paterson, D. Gareth Evans, Jenny Mattison, Gillian Mitchell, Ruth Warren, and Lucy Burgess
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Genes, BRCA2, Population, Genes, BRCA1, Breast Neoplasms, Breast cancer, Internal medicine, medicine, Humans, Mammography, Genetic Predisposition to Disease, Breast, Risk factor, skin and connective tissue diseases, education, Germ-Line Mutation, Gynecology, education.field_of_study, medicine.diagnostic_test, business.industry, Cancer, Hormone replacement therapy (menopause), Odds ratio, Middle Aged, medicine.disease, Relative risk, Female, business
Abstract: High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (Ptrend = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of ≥50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers. (Cancer Res 2006; 66(3): 1866-72)
Published: 2006
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50. Abstract 2258: Genome-wide association studies of breast cancer prognosis

Author: Renske Keeman, Jacques Simard, Douglas F. Easton, Peter Kraft, Marjanka K. Schmidt, Qi Guo, Thilo Dörk, Diana Eccles, and Paul D.P. Pharoah
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Breast cancer, business.industry, Internal medicine, medicine, Cancer, Genome-wide association study, business, medicine.disease
Abstract: Introduction: The prognosis and response to treatment in women with breast cancer varies considerably after taking into account clinic-pathological variables. Other factors such as host genotype are also likely to be important. We therefore investigated the role of germline genetic variation on survival after breast cancer using data from the Breast Cancer Association Consortium. Materials and methods: We included data from ten projects in which breast cancer case cohorts were genotyped using arrays providing genome-wide coverage of common variants. The majority of samples was genotyped using the Illumina custom iCOGS or OncoArray chips. Data were imputed using the 1000 Genome phase 3 as a reference panel using a two-stage procedure. We assessed the association between genotype and 10-year breast cancer specific survival for each SNP using Cox proportional hazards regression adjusted for principle components and stratified by country. Genotype data from 87,877 breast cancer cases, 63,170 ER-positive and 20,297 ER-negative, with 6,511 known breast cancer deaths were included in the analyses. Results: Preliminary analyses shows that in all invasive cases, ER-positive and ER-negative disease 123, 110, and 212 variants respectively, were associated with breast cancer-specific mortality at P Conclusion: We have identified a novel set of germline genetic variants that are associated with breast cancer prognosis. The effect sizes are small for each of the variants and unlikely to be of immediate clinical relevance. However, understanding of the biology that underlies the associations may identify novel pathways and targets for therapy. Being at higher risk of breast cancer, as defined by the breast cancer susceptibility PRS, is not associated with an adverse prognosis. Citation Format: Marjanka K. Schmidt, Qi Guo, Thilo Dörk, Diana Eccles, Renske Keeman, Jacques Simard, Peter Kraft, Douglas F. Easton, Paul D. Pharoah, on behalf of the Breast Cancer Association Consortium. Genome-wide association studies of breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2258. doi:10.1158/1538-7445.AM2017-2258
Published: 2017
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