Citations 9
Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci
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Oncotarget | June 15, 2017 | Volume: 8 | Issue: 39 | Pages: 64670-64684
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
Southey, Melissa C. , Goldgar, David E, Winqvist, Robert , Pylkäs, Katri , Michailidou, Kyriaki , Rensburg, Elizabeth J. van , Heikkinen, Tuomas , Hopper, John L. , Dörk, Thilo , Claes, Kathleen , Teo, Zhi L. , Radice, Paolo , Catucci, Irene, Peterlongo, Paolo , Odefrey, Fabrice, Dowty, James G., Schmidt, Marjanka K. , Hogervorst, Frans B.L., Verhoef, Senno, Carpenter, Jane, Clarke, Christine L. , Scott, Rodney J. , Fasching, Peter A. , Haeberle, Lothar, Ekici, Arif B. , Beckmann, Matthias W. , Peto, Julian , Fletcher, Olivia , Johnson, Nichola , Bolla, Manjeet K. , Sawyer, Elinor J. , Tomlinson, Ian , Kerin, Michael J. , Miller, Nicola, Marmé, F., Burwinkel, Barbara , Guénel, Pascal , Truong, Thérèse , Sanchez, Marie, Bojesen, Stig E. , Nielsen, Sune F. , Flyger, Henrik, Benı́tez, Javier , Zamora, M. Pilar , Menéndez, Primitiva, Brenner, Hermann , Stegmaier, Christa, Brauch, Hiltrud , Brüning, Thomas , Ko, Yon‐Dschun, Muranen, Taru , Aittomäki, Kristiina, Blomqvist, Carl , Bogdanova, Natalia , Antonenkova, Natalia, Lindblom, Annika , Margolin, Sara , Mannermaa, Arto, Kataja, Vesa , Kosma, Veli‐Matti , Hartikainen, Jaana M. , Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wauters, Els , Smeets, Dominiek, Beuselinck, Benoit , Floris, Giuseppe , Chang‐Claude, Jenny , Flesch‐Janys, Dieter, Vachon, Celine M. , McLean, Catriona , Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick R. , Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei , Hunter, David J. , Lindström, Sara, Hankinson, Susan E. , Kraft, Peter , Andrulis, Irene L. , Knight, Julia A. , Glendon, Gord, Mulligan, Anna Marie , Jukkola‐Vuorinen, Arja , Grip, Mervi, Kauppila, Saila , Devilee, Peter , Tollenaar, Robert A.E.M., Seynaeve, Caroline, García‐Closas, Montserrat , Figueroa, Jonine D. , Lissowska, Jolanta , Darabi, Hatef, Eriksson, Mikael , Eccles, Diana M, Tapper, William , Gerty, Sue, Hooning, Maartje J. , Collée, J. Margriet, Tilanus‐Linthorst, Madeleine M.A., Li, Jingmei , Brand, Judith S. , Humphreys, Keith , Reed, Malcolm , Luccarini, Craig , Baynes, Caroline, Dunning, Alison M. , Hamann, Ute, Torres, Diana , Ulmer, Hans Ulrich, Rüdiger, Thomas , Jakubowska, Anna , Lubiński, Jan , Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Yannoukakos, Drakoulis , Swerdlow, Anthony J. , Ashworth, Alan , Orr, Nick , Jones, Michael E. , González‐Neira, Anna , Pita, Guillermo , Alonso, M. Rosario, Álvarez, Núria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel , Bacot, François, Simard, Jacques , Dumont, Martine , Soucy, Penny, Eeles, Rosalind A. , Muir, Kenneth , Grönberg, Henrik , Schleutker, Johanna , Nordestgaard, Børge G. , Weischer, Maren , Travis, Ruth C. , Neal, David E. , Donovan, Jenny , Hamdy, Freddie C. , Stanford, Janet L. , Blot, William J. , Thibodeau, Stephen N. , Schaid, Daniel J. , Kelley, Joseph L., Maier, Christiane, Kibel, Adam S. , Butterbach, Katja, Kaneva, Radka , Batra, Jyotsna , Teixeira, Manuel R. , Olama, Ali Amin Al , Benlloch, Sara, Hartmann, Arndt , Hein, Alexander , Ruebner, Matthias , Lambrechts, Diether , Nieuwenhuysen, Els Van , Vergote, Ignace , Lambretchs, Sandrina, Rossing, Mary Anne, Nickels, Stefan , Eilber, Ursula, Wang‐Gohrke, Shan , Odunsi, Kunle , Sucheston‐Campbell, Lara, Friel, Grace , Lurie, Galina, Killeen, Jeffrey , Goodman, Marc T. , Runnebaum, Ingo B., Hillemanns, Peter , Pelttari, Liisa M. , Edwards, Robert P., Ness, Roberta B., Moysich, Kirsten B., Heitz, Florian , Harter, Philipp , Kommoss, Stefan , Walsh, Christine , Lester, Jenny, Jensen, Allan , Høgdall, Estrid , Peissel, Bernard , Bernard, Loris, Goode, Ellen L. , Vierkant, Robert A. , Cunningham, Julie M. , Fogarty, Zachary C. , Kalli, Kimberly R., Liang, Dong , Lu, Karen H., Hildebrandt, Michelle A.T., Wu, Xifeng , Levine, Douglas A. , Bisogna, Maria, Iversen, Edwin S., Marks, Jeffrey R. , Akushevich, Lucy , Schildkraut, Joellen M. , Terry, Kathryn L. , Stampfer, Meir J. , Tworoger, Shelley S. , Olson, Sara H. , Salvesen, Helga B., Altena, Anne M. van , Aben, Katja K.H. , Kiemeney, Lambertus A. , Massuger, Leon F.A.G. , Bean, Yukie T., Kelemen, Linda E., Le, Nhu D. , Górski, Bohdan , Menkiszak, Janusz , Høgdall, Claus , Lundvall, Lene, Nedergaard, Lotte , Engelholm, Svend Aage, Dicks, Ed , Campbell, Ian , McNeish, Iain A. , Whittemore, Alice S. , Rothstein, Joseph H. , McGuire, Valerie, Sieh, Weiva , Cai, Hui , Teten, Rachel Threet, Sutphen, Rebecca , McLaughlin, John R, Narod, Steven A., Phelan, Catherine M., Monteiro, Álvaro N.A. , Fenstermacher, David, Lin, Hui‐Yi , Sellers, Thomas A. , Chen, Y. Ann , Chen, Zhihua , Gayther, Simon A. , Ramus, Susan J. , Menon, Usha , Wu, Anna H. , Pearce, Celeste Leigh, Pike, Malcolm C., Dansonka‐Mieszkowska, Agnieszka , Plisiecka-Hałasa, Joanna, Moes-Sosnowska, Joanna , Kupryjańczyk, Jolanta , Song, Honglin , Winship, Ingrid , Chenevix‐Trench, Georgia , Tavtigian, Sean V. , Easton, Doug , Lu, Karen H. , Durocher, Francine , Eccles, Diana , Lambrechts, Diether , Vachon, Celine, Pankratz, Vernon S, Thibodeau, Stephen, Goldgar, David E, Couch, Fergus J. , Tischkowitz, Marc D. , Foulkes, William D. , Dennis, Joe , Nevanlinna, Heli , Reis‐Filho, Jorge S. , Tsimiklis, Helen , Broeks, Annegien , dos‐Santos‐Silva, Isabel , Yang, Rongxi , Ménégaux, F. , Sanchez, Marie, Pérez, José Ignacio Arias , Anton‐Culver, Hoda , Neuhausen, Susan L. , Ziogas, Argyrios , Clarke, Christina A. , Arndt, Volker , Mannermaa, Arto, Spurdle, Amanda B. , Group, Australian Ovarian Cancer Study, Rudolph, Anja , Seibold, Petra , Olson, Janet E. , Vachon, Celine M. , Pankratz, V. Shane , Marchand, Loı̈c Le , Kristensen, Vessela N. , Hankinson, Susan E. , Hollestelle, Antoinette , Chanock, Stephen Jacob , Czene, Kamila , Eriksson, Mikael , Eccles, Diana M, Rafiq, Sajjad , Hooning, Maartje J. , Martens, John W.M. , Hall, Per N , Cox, Angela , Toland, Amanda Ewart , Ambrosone, Christine B. , Wiklund, Fredrik E. , Khaw, Kay‐Tee , Cybulski, Cezary , Cannon‐Albright, Lisa , Park, Jong, Kote‐Jarai, Zsofia , Renner, Stefan P. , Doherty, Jennifer A. , Wilkens, Lynne R. , Bützow, Ralf C. , Modugno, Francesmary , Moysich, Kirsten B., Bois, Andreas du , Karlan, Beth Y. , Kjær, Susanne K. , Bonanni, Bernardo , Fridley, Brooke L. , Larson, Melissa C. , Hildebrandt, Michelle A.T. , Dao, Fanny , Berchuck, Andrew , Cramer, Daniel W. , Poole, Elizabeth M. , Bandera, Elisa V. , Orlow, Irene , Bjørge, Line , Pejovic, Tanja B. , Brooks‐Wilson, Angela , Cook, Linda S. , Gronwald, Jacek , Tyrer, Jonathan P. , Paul, James , Siddiqui, Nadeem , Glasspool, Rosalind , Shu, Xiao‐Ou , McLaughlin, John R, Permuth, Jennifer B. , Gentry‐Maharaj, Aleksandra , Berg, David Van Den , Pharoah, Paul D.P. , Giles, Graham G. , Milne, Roger L. , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , McNeish, Iain A , Peterlongo, Paolo , Ramus, Susan J , Teixeira, Manuel R , Tworoger, Shelley S , van Rensburg, Elizabeth J , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Monteiro, Alvaro N , Swerdlow, Anthony J , Moysich, Kirsten , Radice, Paolo , Lissowska, Jolanta , Claes, Kathleen B M , Campbell, Ian G , Eeles, Rosalind A , Southey, Melissa C , Menkiszak, Janusz , Donovan, Jenny L , Muir, Kenneth , Schleutker, Johanna , Travis, Ruth C , Lin, Hui-Yi , Fogarty, Zachary C , Dunning, Alison M , Heitz, Florian , Jakubowska, Anna , Jones, Michael E , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Brenner, Hermann , Guénel, Pascal , Li, Jingmei , Muranen, Taru A , Torres, Diana , García-Closas, Montserrat , Schmidt, Marjanka K , Winship, Ingrid M , Ekici, Arif B , Michailidou, Kyriaki , Hartikainen, Jaana M , Bogdanova, Natalia V , Kraft, Peter , Benitez, Javier , Simard, Jacques , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Høgdall, Estrid , Høgdall, Claus K , Batra, Jyotsna , Pylkäs, Katri , Yannoukakos, Drakoulis , Devilee, Peter , Lubinski, Jan , Fletcher, Olivia , Bojesen, Stig E , Goodman, Marc T , Truong, Therese , Mclean, Catriona , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Orr, Nick
Journal of Medical Genetics | September 5, 2016 | Volume: 53 | Issue: 12 | Pages: 800-811
Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer
Painter, Jodie N. , O’Mara, Tracy A. , Marquart, Louise , Webb, Penelope M. , Medland, Sarah E. , Cheng, Timothy, Holliday, Elizabeth , McEvoy, Mark , Scott, Rodney J. , Healey, Catherine S., Shah, Mitul , Gorman, Maggie, Martin, Lynn , Hodgson, Shirley V. , Beckmann, Matthias W. , Ekici, Arif B. , Fasching, Peter A. , Hein, Alexander , Rübner, Matthias, Darabi, Hatef, Li, Jingmei , Dörk, Thilo , Hillemanns, Peter , Runnebaum, Ingo B. , Annibali, Daniela , Depreeuw, Jeroen, Lambrechts, Diether , Neven, Patrick , Cunningham, Julie M. , Dowdy, Sean C. , Goode, Ellen L. , Winham, Stacey J. , Njølstad, Tormund S. , Salvesen, Helga B., Trovik, Jone , Werner, Henrica M.J., Ashton, Katie A. , Otton, Geoffrey, Proietto, Anthony , Mints, Miriam, Tham, Emma , Bolla, Manjeet K. , Michailidou, Kyriaki , Wang, Qin , Hopper, John L. , Peto, Julian , Swerdlow, Anthony J. , Burwinkel, Barbara , Brenner, Hermann , Meindl, Alfons, Brauch, Hiltrud , Lindblom, Annika , Chang‐Claude, Jenny , Couch, Fergus J. , Kristensen, Vessela N. , Tomlinson, Ian M., Dunning, Alison M. , Easton, Douglas F. , Thompson, Deborah J. , Lambrechts, Diether , Attia, John , Dennis, Joe , Ahmed, Shahana , Czene, Kamila , Hall, Per N , Dürst, Matthias , Amant, Frédéric , Fridley, Brooke L. , Mints, Miriam , Tyrer, Jonathan P. , Meindl, Alfons, Couch, Fergus J. , Giles, Graham G. , Cox, Angela , Pharoah, Paul D.P. , Spurdle, Amanda B. , Winham, Stacey J , Dörk, Thilo , Lambrechts, Diether , Webb, Penelope M , Hein, Alexander , Hillemanns, Peter , Swerdlow, Anthony J , Medland, Sarah E , O'Mara, Tracy A , Dunning, Alison M , Lambrechts, Diether , Brenner, Hermann , Li, Jingmei , Ekici, Arif B , Michailidou, Kyriaki , Brauch, Hiltrud , Lindblom, Annika
Cancer Epidemiology, Biomarkers & Prevention | August 22, 2016 | Volume: 25 | Issue: 11 | Pages: 1503-1510
Abstract Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.
Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types
Kar, Siddhartha , Beesley, Jonathan, Olama, Ali Amin Al , Michailidou, Kyriaki , Lawrenson, Kate , Lindström, Sara, Ramus, Susan J. , Thompson, Deborah J. , Investigators, ABCTB, Kibel, Adam S. , Dansonka‐Mieszkowska, Agnieszka , Michael, Agnieszka , Dieffenbach, Aida Karina, Whittemore, Alice S. , Monteiro, Álvaro N.A. , Peixoto, Ana , González‐Neira, Anna , Wu, Anna H. , Lindblom, Annika , Swerdlow, Anthony J. , Cancer), AOCS Study Group & Australian Cancer Study (Ovarian, BioResource, APCB, Ekici, Arif B. , Burwinkel, Barbara , Nordestgaard, Børge G. , Blomqvist, Carl , Phelan, Catherine, McLean, Catriona , Pearce, Celeste Leigh, Vachon, Celine M. , Stegmaier, Christa, Maier, Christiane, Høgdall, Claus , Kang, Daehee , Tessier, Daniel C., Schaid, Daniel J. , Neal, David E. , Eccles, Diana , Flesch‐Janys, Dieter, Wokozorczyk, Dominika, Levine, Douglas A. , Yannoukakos, Drakoulis , Sawyer, Elinor J. , Goode, Ellen L. , Хуснутдинова, Э. К. , Høgdall, Estrid , Song, Fengju, Bruinsma, Fiona, Heitz, Florian , Hamdy, Freddie C. , Olsson, Håkan , Wildiers, Hans , Ulmer, Hans-Ulrich, Pandha, Hardev , Darabi, Hatef, Salvesen, Helga B., Grönberg, Henrik , Brenner, Hermann , Brauch, Hiltrud , Song, Honglin , Lim, Hui-Yi, McNeish, Iain A. , Campbell, Ian , Vergote, Ignace , Lubiński, Jan , Stanford, Janet L. , Benı́tez, Javier , Chang‐Claude, Jenny , Donovan, Jenny , Schildkraut, Joellen M. , Schleutker, Johanna , Hopper, John L. , Kupryjańczyk, Jolanta , Figueroa, Jonine D. , Clements, Judith A. , Knight, Julia A. , Peto, Julian , Cunningham, Julie M. , Pow‐Sang, Julio M. , Batra, Jyotsna , Lu, Karen H., Herkommer, Kathleen , Investigators, kConFab, Matsuo, Keitaro , Muir, Kenneth , Offitt, Kenneth, Chen, Kexin , Moysich, Kirsten B., Aittomäki, Kristiina, Odunsi, Kunle , Kiemeney, Lambertus A. , Massuger, Leon F.A.G. , Hooning, Maartje J. , Pike, Malcolm C., Bolla, Manjeet K. , Luedeke, Manuel, Teixeira, Manuel R. , Goodman, Marc T. , Schmidt, Marjanka K. , Riggan, Marjorie J. , Rossing, Mary Anne, Beckmann, Matthias W. , Moisse, Matthieu , Southey, Melissa C. , Jones, Michael E. , Hildebrandt, Michelle A.T., Hou, Ming‐Feng , Schoemaker, Minouk J. , García‐Closas, Montserrat , Bogdanova, Natalia , Investigators, NBCS, Le, Nhu D. , Orr, Nick , Wentzensen, Nicolas , Pashayan, Nora , Peterlongo, Paolo , Guénel, Pascal , Brennan, Paul , Paulo, Paula , Webb, Penelope M. , Broberg, Per, Fasching, Peter A. , Devilee, Peter , Wang, Qin, Kaneva, Radka , Kopperud, Reidun Kristin, Schmutzler, Rita K., Stephenson, Robert A., MacInnis, Robert J. , Hoover, Robert N. , Winqvist, Robert , Ness, Roberta B., Travis, Ruth C. , Benlloch, Sara, Olson, Sara H. , McDonnell, Shannon K. , Tworoger, Shelley S. , Maia, Sofia , Berndt, Sonja I., Lee, Soo Chin , Teo, Soo‐Hwang , Thibodeau, Stephen N. , Bojesen, Stig E. , Gapstur, Susan M. , Tammela, Teuvo L.J. , Network, the GENICA, Dörk, Thilo , Brüning, Thomas , Wahlfors, Tiina , Edwards, Todd L., Menon, Usha , Hamann, Ute , Mitev, Vanio , Kosma, Veli‐Matti , Setiawan, Veronica Wendy , Kristensen, Vessela, Vogel, Walther , Zheng, Wei , Sieh, Weiva , Blot, William J. , Kluźniak, Wojciech , Gao, Yu‐Tang , Schumacher, Fredrick R. , Freedman, Matthew L., Dunning, Alison M. , Simard, Jacques , Haiman, Christopher A. , Sellers, Thomas A. , Hunter, David J. , Henderson, Brian E., Kraft, Peter , Gayther, Simon A. , Easton, Douglas F. , Chenevix‐Trench, Georgia , Eeles, Rosalind A. , Lambrechts, Diether , Lu, Karen H. , Durocher, Francine , Zheng, Wei , Thorne, Heather , Lambrechts, Diether , Chen, Kexin , Vachon, Celine, Tyrer, Jonathan P. , Kote‐Jarai, Zsofia , Investigators, ABCTB, Gentry‐Maharaj, Aleksandra , Wolk, Alicja , Kierzek, Andrzej , Cox, Angela , Rudolph, Anja , Cancer), AOCS Study Group & Australian Cancer Study (Ovarian, BioResource, APCB, Ziogas, Argyrios , Karlan, Beth Y. , Vachon, Celine M. , Cybulski, Cezary , Slavov, Chavdar , Ambrosone, Christine B. , Teerlink, Craig C. , Stram, Daniel O. , Cramer, Daniel W. , Edwards, Digna R. Velez , Bandera, Elisa V. , Poole, Elizabeth M. , Song, Fengju , Modugno, Francesmary , Wiklund, Fredrik E. , Giles, Graham G. , Risch, Harvey A. , Nevanlinna, Heli , Anton‐Culver, Hoda , Gronwald, Jacek , Doherty, Jennifer A. , Permuth, Jennifer B. , Dennis, Joe , Park, Jong Y. , Czene, Kamila , Khaw, Kay‐Tee , Investigators, kConFab, Moysich, Kirsten B., FitzGerald, Liesel M. , Cook, Linda S. , Cannon‐Albright, Lisa , Hooning, Maartje J. , Aly, Markus , Sanderson, Maureen , Lush, Michael J. , Hildebrandt, Michelle A.T. , Rahman, Nazneen , Investigators, NBCS, Wang, Qin, Cai, Qiuyin , Li, Qiyuan , Bützow, Ralf C. , Milne, Roger L. , Berndt, Sonja I. , Kjær, Susanne K. , Pejovic, Tanja B. , Network, the GENICA, Key, Tim , Kristensen, Vessela N. , Arndt, Volker , Shu, Xiao‐Ou , Berchuck, Andrew , Spurdle, Amanda B. , Chanock, Stephen Jacob , Couch, Fergus J. , Hall, Per N , Pharoah, Paul D.P. , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , McNeish, Iain A , Peterlongo, Paolo , Ramus, Susan J , Teixeira, Manuel R , Teo, Soo H , Tworoger, Shelley S , Webb, Penelope M , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Monteiro, Alvaro N , Swerdlow, Anthony J , Moysich, Kirsten , Campbell, Ian G , Eeles, Rosalind A , Southey, Melissa C , Donovan, Jenny L , Muir, Kenneth , Schleutker, Johanna , Travis, Ruth C , Pashayan, Nora , Michael, Agnieszka , Maclnnis, Robert , Matsuo, Keitaro , Dunning, Alison M , Heitz, Florian , Jones, Michael E , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Brenner, Hermann , Guénel, Pascal , García-Closas, Montserrat , Schmidt, Marjanka K , Ekici, Arif B , Moisse, Matthieu , Michailidou, Kyriaki , Bogdanova, Natalia V , Kraft, Peter , Benitez, Javier , Simard, Jacques , Chenevix-Trench, Georgia , Zheng, Wei , Figueroa, Jonine D , Høgdall, Estrid , Høgdall, Claus K , Kar, Siddhartha , Batra, Jyotsna , Clements, Judith , Setiawan, Veronica W , Yannoukakos, Drakoulis , Devilee, Peter , Lubinski, Jan , Bojesen, Stig E , Schoemaker, Minouk J , Goodman, Marc T , Wildiers, Hans , Mclean, Catriona , Brauch, Hiltrud , Lindblom, Annika , Sawyer, Elinor J , Orr, Nick , McDonnell, Shannon K , Kang, Daehee
Cancer Discovery | July 18, 2016 | Volume: 6 | Issue: 9 | Pages: 1052-1067
Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932
Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer
Hampras, Shalaka , Sucheston‐Campbell, Lara, Cannioto, Rikki , Chang‐Claude, Jenny , Dörk, Thilo , Hillemanns, Peter , Preus, Leah, Knutson, Keith L. , Wallace, Paul K. , Friel, Grace , Davis, Warren , Nesline, Mary , Pearce, Celeste Leigh, Kelemen, Linda E. , Goodman, Marc T. , Terry, Kathryn L. , Schoof, Nils , Eng, Kevin H., Clay‐Gilmour, Alyssa , Joseph, Janine M. , Aben, Katja K.H. , Antonenkova, Natalia, Baker, Helen , Bean, Yukie T., Beckmann, Matthias W. , Bisogna, Maria, Bogdanova, Natalia , Brinton, Louise A. , Bruinsma, Fiona , Campbell, Ian , Carty, Karen , Dansonka‐Mieszkowska, Agnieszka , Despierre, Evelyn, Dicks, Ed , Easton, Doug , Eccles, Diana , Edwards, Robert P., Ekici, Arif B. , Fasching, Peter A. , Gao, Yu‐Tang , Harrington, Patricia, Harter, Philipp , Hasmad, Hanis Nazihah, Hein, Alexander , Heitz, Florian , Hildebrandt, Michelle A.T., Høgdall, Claus , Høgdall, Estrid , Hosono, Satoyo , Iversen, Edwin S., Jakubowska, Anna , Jensen, Allan , Ji, Bu‐Tian , Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A. , Klapdor, Rüdiger , Kolomeyevskaya, Nonna, Krakstad, Camilla , Kruszka, Bridget, Kupryjańczyk, Jolanta , Lambrechts, Diether , Lambrechts, Sandrina, Le, Nhu D. , Lee, Alice W. , Lele, Shashikant , Leminen, Arto, Lester, Jenny, Levine, Douglas A. , Liang, Dong , Lissowska, Jolanta , Liu, Song , Lu, Karen, Lubiński, Jan , Lundvall, Lene, Massuger, Leon F.A.G. , Matsuo, Keitaro , McGuire, V., McLaughlin, John R., McNeish, Iain A. , Menon, Usha , Moes-Sosnowska, Joanna , Narod, Steven A., Nedergaard, Lotte , Nickels, Stefan , Olson, Sara H. , Weber, Rachel Palmieri , Paul, James , Pelttari, Liisa M. , Perkins, Barbara, Permuth‐Wey, Jenny, Pike, Malcolm C., Plisiecka-Hałasa, Joanna, Rossing, Mary Anne, Rothstein, Joseph H. , Runnebaum, Ingo B. , Rzepecka, Iwona K. , Salvesen, Helga B., Schernhammer, Eva , Schmitt, Kristina, Schwaab, Ira, Shvetsov, Yurii B. , Sieh, Weiva , Song, Honglin , Southey, Melissa C. , Tangen, Ingvild L. , Teo, Soo‐Hwang , Thompson, Pamela J., Timorek, Agnieszka, Tworoger, Shelley S. , Altena, Anna M. van, Vergote, Ignace , Vierkant, Robert A. , Walsh, Christine , Wang‐Gohrke, Shan , Wentzensen, Nicolas, Whittemore, Alice S. , Wicklund, Kristine G. , Wu, Anna H. , Wu, Xifeng , Woo, Yin Ling , Zheng, Wei , Gayther, Simon A. , Ramus, Susan J. , Sellers, Thomas A. , Schildkraut, Joellen M. , Phelan, Catherine M., Chenevix‐Trench, Georgia , Cunningham, Julie M. , Ness, Roberta B., Odunsi, Kunle , Goode, Ellen L. , Moysich, Kirsten B., Lu, Karen H. , Lambrechts, Diether , Modugno, Francesmary , Knutson, Keith L. , Hong, Chi‐Chen , Bandera, Elisa V. , Singh, Prashant Kumar , Anton‐Culver, Hoda , Bjørge, Line , Brooks‐Wilson, Angela , Bützow, Ralf C. , Cook, Linda S. , Cramer, Daniel W. , Cybulski, Cezary , Dennis, Joe , Doherty, Jennifer A. , Bois, Andreas du , Dürst, Matthias , Fridley, Brooke L. , Gentry‐Maharaj, Aleksandra , Giles, Graham G. , Glasspool, Rosalind , Gronwald, Jacek , Hildebrandt, Michelle A.T. , Karlan, Beth Y. , Kjær, Susanne K. , Lu, Karen, McLaughlin, John R., Nevanlinna, Heli , Orlow, Irene , Pejovic, Tanja B. , Poole, Elizabeth M. , Risch, Harvey A. , Rudolph, Anja , Shu, Xiao‐Ou , Siddiqui, Nadeem , Tyrer, Jonathan P. , Wentzensen, Nicolas , Wilkens, Lynne R. , Yang, Hannah , Ziogas, Argyrios , Berchuck, Andrew , Pharoah, Paul D.P. , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , McNeish, Iain A , Ramus, Susan J , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Paul, James , Moysich, Kirsten , Lissowska, Jolanta , Campbell, Ian G , Southey, Melissa C , Matsuo, Keitaro , Heitz, Florian , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Bogdanova, Natalia V , Chenevix-Trench, Georgia , Zheng, Wei , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T
Oncotarget | July 6, 2016 | Volume: 7 | Issue: 43 | Pages: 69097-69110
Epithelial‐Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk
Amankwah, Ernest K. , Lin, Hui‐Yi , Lawrenson, Kate , Chornokur, Ganna , Aben, Katja K.H. , Antonenkova, Natalia, Bruinsma, Fiona , Bean, Yukie T., Beckmann, Matthias W. , Bisogna, Maria, Bogdanova, Natalia , Brinton, Louise A. , Campbell, Ian , Chen, Zhihua , Chen, Y. Ann , Chang‐Claude, Jenny, Cunningham, Julie M. , Dansonka‐Mieszkowska, Agnieszka , Despierre, Evelyn, Dicks, Ed , Dörk, Thilo , Easton, Douglas F. , Eccles, Diana M., Edwards, Robert P., Ekici, Arif B. , Fasching, Peter A. , Gao, Yu‐Tang , Giles, Graham G. , Glasspool, Rosalind , Goodman, Marc T. , Harrington, Patricia, Harter, Philipp , Hasmad, Hanis Nazihah, Hein, Alexander , Heitz, Florian , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Claus , Høgdall, Estrid , Hosono, Satoyo , Iversen, Edwin S., Jakubowska, Anna , Jensen, Allan , Ji, Bu‐Tian , Kellar, Melissa, Kiemeney, Lambertus A. , Krakstad, Camilla , Kupryjańczyk, Jolanta , Lambrechts, Diether , Lambrechts, Sandrina, Le, Nhu D. , Lee, Alice W. , Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A. , Liang, Dong , Lim, Boon Kiong , Lissowska, Jolanta , Lu, Karen, Lubiński, Jan , Lundvall, Lene, Massuger, Leon F.A.G. , Matsuo, Keitaro , McGuire, Valerie , McLaughlin, John R., McNeish, Iain A. , Menon, Usha , Moysich, Kirsten B., Ness, Roberta B., Eilber, Ursula, Odunsi, Kunle , Olson, Sara H. , Orlow, Irene , Oršulić, Sandra , Weber, Rachel Palmieri , Pearce, Celeste Leigh, Pelttari, Liisa M. , Permuth‐Wey, Jennifer, Pike, Malcolm C., Rossing, Mary Anne, Rothstein, Joseph H. , Runnebaum, Ingo B. , Rzepecka, Iwona K. , Salvesen, Helga B., Schernhammer, Eva , Schwaab, Ira, Shu, Xiao‐Ou, Shvetsov, Yurii B. , Sieh, Weiva , Song, Honglin , Southey, Melissa C. , Śpiewankiewicz, Beata, Sucheston‐Campbell, Lara, Teo, Soo‐Hwang , Terry, Kathryn L. , Thompson, Pamela J., Tangen, Ingvild L. , Tworoger, Shelley S. , Altena, Anne M. van , Vierkant, Robert A. , Vergote, Ignace , Walsh, Christine , Wang‐Gohrke, Shan , Wentzensen, Nicolas, Whittemore, Alice S. , Wicklund, Kristine G. , Wu, Anna H. , Wu, Xifeng , Woo, Yin Ling , Zheng, Wei , Kelemen, Linda E. , group, Georgia Chenevix‐Trench on behalf of the AOCS management, Schildkraut, Joellen M. , Ramus, Susan J. , Goode, Ellen L. , Monteiro, Álvaro N.A. , Gayther, Simon A. , Narod, Steven A., Sellers, Thomas A. , Phelan, Catherine M., Lu, Karen H. , Eccles, Diana , Lambrechts, Diether , Tyrer, Jonathan P. , Dennis, Joe , Anton‐Culver, Hoda , Bandera, Elisa V. , Bjørge, Line , Brooks‐Wilson, Angela , Bunker, Clareann H. , Bützow, Ralf C. , Carty, Karen , Cook, Linda S. , Cramer, Daniel W. , Cybulski, Cezary , Bois, Andreas du , Doherty, Jennifer A. , Dürst, Matthias , Eccles, Diana M., Fridley, Brooke L. , Gentry‐Maharaj, Aleksandra , Gronwald, Jacek , Hildebrandt, Michelle A.T. , Karlan, Beth Y. , Jim, Heather , Kjær, Susanne K. , Lu, Karen, McLaughlin, John R., Milne, Roger L. , Modugno, Francesmary , Nevanlinna, Heli , Paul, James , Pejovic, Tanja B. , Poole, Elizabeth M. , Risch, Harvey A. , Rosen, Barry P. , Rudolph, Anja , Siddiqui, Nadeem , Thomsen, Lotte Nedergaard , Wentzensen, Nicolas , Wilkens, Lynne R. , Yang, Hannah , Ziogas, Argyrios , Berchuck, Andrew , group, Georgia Chenevix‐Trench on behalf of the AOCS management, Pharoah, Paul D.P. , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , Kiemeney, Lambertus A , McNeish, Iain A , Ramus, Susan J , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Monteiro, Alvaro N , Moysich, Kirsten , Orlow, Irene , Lissowska, Jolanta , Campbell, Ian G , Southey, Melissa C , Glasspool, Rosalind , Lin, Hui-Yi , Matsuo, Keitaro , Heitz, Florian , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Bogdanova, Natalia V , Zheng, Wei , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T
Genetic Epidemiology | September 24, 2015 | Volume: 39 | Issue: 8 | Pages: 689-697
ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
Network-Based Integration of GWAS and Gene Expression Identifies a HOX -Centric Network Associated with Serous Ovarian Cancer Risk
Kar, Siddhartha , Lawrenson, Kate , Aben, Katja K.H. , Antonenkova, Natalia, Chenevix‐Trench, Georgia , Study, on behalf of the Australian Cancer, Group, and on behalf of the Australian Ovarian Cancer Study, Baker, Helen , Bean, Yukie T., Beckmann, Matthias W. , Bisogna, Maria, Bogdanova, Natalia , Brinton, Louise A. , Campbell, Ian , Carty, Karen , Chang‐Claude, Jenny , Chen, Y. Ann , Chen, Zhihua , Cunningham, Julie M. , Dansonka‐Mieszkowska, Agnieszka , Dicks, Ed , Dörk, Thilo , Eccles, Diana , Easton, Douglas F. , Edwards, Robert P., Ekici, Arif B. , Fasching, Peter A. , Gao, Yu‐Tang , Giles, Graham G. , Glasspool, Rosalind , Goode, Ellen L. , Goodman, Marc T. , Grownwald, Jacek, Harrington, Patricia, Harter, Philipp , Hein, Alexander , Heitz, Florian , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Estrid , Høgdall, Claus , Hosono, Satoyo , Iversen, Edwin S., Jakubowska, Anna , Jensen, Allan , Ji, Bu‐Tian , Kjær, Susanne K. , Kelemen, Linda E. , Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A. , Krakstad, Camilla , Kupryjańczyk, Jolanta , Lambrechts, Diether , Lambrechts, Sandrina, Le, Nhu D. , Lee, Alice W. , Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A. , Liang, Dong , Lissowska, Jolanta , Lu, Karen, Lubiński, Jan , Lundvall, Lene, Massuger, Leon F.A.G. , Matsuo, Keitaro , McGuire, Valerie , McLaughlin, John R., McNeish, Iain A. , Menon, Usha , Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte , Ness, Roberta B., Odunsi, Kunle , Olson, Sara H. , Orlow, Irene , Oršulić, Sandra , Weber, Rachel Palmieri , Pearce, Celeste Leigh, Pelttari, Liisa M. , Permuth‐Wey, Jennifer, Phelan, Catherine M., Pike, Malcolm C., Ramus, Susan J. , Rossing, Mary Anne, Rothstein, Joseph H. , Runnebaum, Ingo B. , Rzepecka, Iwona K. , Salvesen, Helga B., Schildkraut, Joellen M. , Schwaab, Ira, Shvetsov, Yurii B. , Sieh, Weiva , Song, Honglin , Southey, Melissa C. , Sucheston‐Campbell, Lara, Tangen, Ingvild L. , Teo, Soo‐Hwang , Terry, Kathryn L. , Thompson, Pamela J., Timorek, Agnieszka, Tworoger, Shelley S. , Altena, Anne M. van , Nieuwenhuysen, Els Van , Vergote, Ignace , Vierkant, Robert A. , Wang‐Gohrke, Shan , Walsh, Christine , Wentzensen, Nicolas, Whittemore, Alice S. , Wicklund, Kristine G. , Woo, Yin Ling , Wu, Xifeng , Wu, Anna H. , Zheng, Wei , Sellers, Thomas A. , Monteiro, Álvaro N.A. , Freedman, Matthew L., Gayther, Simon A. , Lu, Karen H. , Lambrechts, Diether , Tyrer, Jonathan P. , Li, Qiyuan , Anton‐Culver, Hoda , Study, on behalf of the Australian Cancer, Group, and on behalf of the Australian Ovarian Cancer Study, Bandera, Elisa V. , Berchuck, Andrew , Bjørge, Line , Brooks‐Wilson, Angela , Bützow, Ralf C. , Cook, Linda S. , Cramer, Daniel W. , Cybulski, Cezary , Dennis, Joe , Doherty, Jennifer A. , Bois, Andreas du , Dürst, Matthias , Fridley, Brooke L. , Gentry‐Maharaj, Aleksandra , Hildebrandt, Michelle A.T. , Paul, James , Karlan, Beth Y. , Lu, Karen, McLaughlin, John R., Modugno, Francesmary , Nevanlinna, Heli , Pejovic, Tanja B. , Poole, Elizabeth M. , Risch, Harvey A. , Rosen, Barry P. , Rudolph, Anja , Shu, Xiao‐Ou , Siddiqui, Nadeem , Wentzensen, Nicolas , Wilkens, Lynne R. , Yang, Hannah , Ziogas, Argyrios , Pharoah, Paul D.P. , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , Kiemeney, Lambertus A , Kjaer, Susanne K , McNeish, Iain A , Ramus, Susan J , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Monteiro, Alvaro N , Moysich, Kirsten , Orlow, Irene , Lissowska, Jolanta , Campbell, Ian G , Southey, Melissa C , Glasspool, Rosalind , Matsuo, Keitaro , Heitz, Florian , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Bogdanova, Natalia V , Chenevix-Trench, Georgia , Zheng, Wei , Høgdall, Estrid , Høgdall, Claus K , Kar, Siddhartha , Lubinski, Jan , Goodman, Marc T
Cancer Epidemiology, Biomarkers & Prevention | July 24, 2015 | Volume: 24 | Issue: 10 | Pages: 1574-1584
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.
Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci
Coetzee, Simon G. , Shen, Howard C., Hazelett, Dennis J. , Lawrenson, Kate , Kuchenbaecker, Karoline , Rhie, Suhn K. , Levanon, Keren , Karst, Alison M., Drapkin, Ronny , Ramus, Susan J. , Offit, Kenneth, Chenevix‐Trench, Georgia , Monteiro, Álvaro N.A. , Antoniou, Antonis C. , Freedman, Matthew L., Coetzee, Gerhard A. , Gayther, Simon A. , Antonenkova, Natalia, Bean, Yukie T., Beckmann, Matthias W. , Bisogna, Maria, Bogdanova, Natalia , Brinton, Louise A. , Bruinsma, Fiona , Chang‐Claude, Jenny, Chen, Ann , Chen, Zhihua , Cunningham, Julie M. , Dansonka‐Mieszkowska, Agnieszka , Dicks, Ed , Dörk, Thilo , Eccles, Diana , Easton, Douglas F. , Edwards, Robert P., Eilber, Ursula, Ekici, Arif B. , Fasching, Peter A. , Gao, Yu‐Tang , Giles, Graham G. , Glasspool, Rosalind , Goode, Ellen L. , Grownwald, Jacek, Harrington, Patricia, Harter, Philipp , Hasmad, Hanis Nazihah, Hein, Alexander , Heitz, Florian , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Claus , Hosono, Satoyo , Iversen, Edwin S., Jakubowska, Anna , James, Paul A. , Jensen, Allan , Ji, Bu‐Tian , Kjær, Susanne K. , Kelemen, Linda E. , Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A. , Krakstad, Camilla , Kupryjańczyk, Jolanta , Lambrechts, Diether , Lambrechts, Sandrina, Le, Nhu D. , Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A. , Lissowska, Jolanta , Lu, Karen, Lubiński, Jan , Lundvall, Lene, Massuger, Leon F.A.G. , Matsuo, Keitaro , McGuire, Valerie , McLaughlin, John R., McNeish, Ian, Menon, Usha , Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte , Ness, Roberta B., Azmi, Mat Adenan Noor, Odunsi, Kunle , Oršulić, Sandra , Pearce, Celeste Leigh, Pelttari, Liisa M. , Permuth‐Wey, Jennifer, Phelan, Catherine M., Pike, Malcolm C., Rossing, Mary Anne, Rothstein, Joseph H. , Runnebaum, Ingo B., Rzepecka, Iwona K. , Salvesen, Helga B., Schildkraut, Joellen M. , Schwaab, Ira, Sellers, Thomas A. , Shu, Xiao‐Ou, Shvetsov, Yurii B. , Sieh, Weiva , Song, Honglin , Southey, Melissa C. , Sucheston, Lara, Tangen, Ingvild L. , Teo, Soo‐Hwang , Thompson, Pamela J., Timorek, Agnieszka, Tworoger, Shelley S. , Altena, Anne M. van , Nieuwenhuysen, Els Van , Vergote, Ignace , Vierkant, Robert A. , Wang‐Gohrke, Shan , Walsh, Christine , Wentzensen, Nicolas, Whittemore, Alice S. , Wicklund, Kristine G. , Woo, Yin Ling , Wu, Xifeng , Wu, Anna H. , Lu, Karen H. , McNeish, Iain A. , Lambrechts, Diether , Tyrer, Jonathan P. , Couch, Fergus J. , Pharoah, Paul D.P. , Noushmehr, Houtan , Anton‐Culver, Hoda , Baker, Helen H. , Bandera, Elisa V. , Berchuck, Andrew , Bjørge, Line , Brooks‐Wilson, Angela , Bützow, Ralf C. , Campbell, Ian , Carty, Karen , Cook, Linda S. , Cramer, Daniel W. , Cybulski, Cezary , Dennis, Joe , Doherty, Jennifer A. , Bois, Andreas du , Dürst, Matthias , Fridley, Brooke L. , Gentry‐Maharaj, Aleksandra , Goodman, Marc T. , Hildebrandt, Michelle A.T. , Høgdall, Estrid , Karlan, Beth Y. , Lester, Jenny, Liang, Dong , Lu, Karen, McLaughlin, John R., McNeish, Ian, Modugno, Francesmary , Olson, Sara H. , Orlow, Irene , Weber, Rachel Palmieri , Pejovic, Tanja B. , Poole, Elizabeth M. , Risch, Harvey A. , Rosen, Barry P. , Rudolph, Anja , Siddiqui, Nadeem , Terry, Kathryn L. , Wentzensen, Nicolas , Wilkens, Lynne R. , Yang, Hannah , Zheng, Wei , Ziogas, Argyrios , Pelttari, L M , Dörk, Thilo , Lambrechts, Diether , Giles, Graham G , James, Paul , Kiemeney, Lambertus A , Kjaer, Susanne K , McNeish, Iain A , Ramus, Susan J , Teo, Soo H , Tworoger, Shelley S , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Hazelett, Dennis J , Coetzee, Simon G , Monteiro, Alvaro N , Lissowska, Jolanta , Southey, Melissa C , Glasspool, Rosalind , Matsuo, Keitaro , Heitz, Florian , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , Ekici, Arif B , Bogdanova, Natalia V , Chenevix-Trench, Georgia , Drapkin, Ronny , Høgdall, Claus K , Lubinski, Jan
Human Molecular Genetics | March 24, 2015 | Volume: 24 | Issue: 13 | Pages: 3595-3607
Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk
Kelemen, Linda E. , Terry, Kathryn L. , Goodman, Marc T. , Webb, Penelope M. , McGuire, Valerie , Rossing, Mary Anne, Wang, Qinggang , Dicks, Ed , Song, Honglin , Kupryjańczyk, Jolanta , Dansonka‐Mieszkowska, Agnieszka , Plisiecka-Hałasa, Joanna, Timorek, Agnieszka, Menon, Usha , Gayther, Simon A. , Ramus, Susan J. , Narod, Steven A., McLaughlin, John R., Glasspool, Rosalind , Lubiński, Jan , Jakubowska, Anna , Kiemeney, Lambertus A. , Massuger, Leon F.A.G. , Altena, Anne M. van , Aben, Katja K.H. , Olson, Sara H. , Orlow, Irene , Levine, Douglas A. , Bisogna, Maria, Southey, Melissa C. , Bruinsma, Fiona , Kjær, Susanne K. , Høgdall, Estrid , Jensen, Allan , Høgdall, Claus , Lundvall, Lene, Engelholm, Svend‐Aage, Harter, Philipp , Schwaab, Ira, Nevanlinna, Heli , Pelttari, Liisa M. , Leminen, Arto, Thompson, Pamela J., Lurie, Galina, Lambrechts, Diether , Nieuwenhuysen, Els Van , Lambrechts, Sandrina, Vergote, Ignace , Beesley, Jonathan, Investigators, AOCS Study Group/ACS, Fasching, Peter A. , Beckmann, Matthias W. , Hein, Alexander , Ekici, Arif B. , Wu, Anna H. , Pearce, Celeste Leigh, Pike, Malcolm C., Chang‐Claude, Jenny , Dörk, Thilo , Hillemanns, Peter , Runnebaum, Ingo B. , Bogdanova, Natalia , Antonenkova, Natalia, Odunsi, Kunle , Edwards, Robert P., Kelley, Joseph L., Ness, Roberta B., Walsh, Christine , Lester, Jenny, Oršulić, Sandra , Vierkant, Robert A. , Cunningham, Julie M. , Wu, Xifeng , Lu, Karen H., Hildebrandt, Michelle A.T., Weber, Rachel Palmieri , Iversen, Edwin S., Tworoger, Shelley S. , Salvesen, Helga B., Tangen, Ingvild L. , Bean, Yukie T., Kellar, Melissa, Wentzensen, Nicolas , Brinton, Louise A. , Lissowska, Jolanta , García‐Closas, Montserrat , Campbell, Ian , Eccles, Diana , Whittemore, Alice S. , Sieh, Weiva , Rothstein, Joseph H. , Phelan, Catherine M., Moysich, Kirsten B., Goode, Ellen L. , Schildkraut, Joellen M. , Sellers, Thomas A. , Le, Nhu D. , Lu, Karen H. , Zheng, Wei , Lambrechts, Diether , Bandera, Elisa V. , Tyrer, Jonathan P. , Gentry‐Maharaj, Aleksandra , Risch, Harvey A. , McLaughlin, John R., Siddiqui, Nadeem , Paul, James , Carty, Karen , Gronwald, Jacek , Cybulski, Cezary , Cramer, Daniel W. , Giles, Graham G. , Heitz, Florian , Bois, Andreas du , Bützow, Ralf C. , Wilkens, Lynne R. , Beesley, Jonathan, Investigators, AOCS Study Group/ACS, Doherty, Jennifer A. , Stram, Daniel O. , Rudolph, Anja , Dürst, Matthias , Modugno, Francesmary , Karlan, Beth Y. , Fridley, Brooke L. , Liang, Dong , Hildebrandt, Michelle A.T. , Poole, Elizabeth M. , Krakstad, Camilla , Bjørge, Line , Pejovic, Tanja B. , Anton‐Culver, Hoda , Ziogas, Argyrios , Berchuck, Andrew , Pharoah, Paul D.P. , Brooks‐Wilson, Angela , Cook, Linda S. , Pelttari, L M , Nevanlinna, H , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , Kjaer, Susanne K , Ramus, Susan J , Tworoger, Shelley S , Webb, Penelope M , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Moysich, Kirsten , Orlow, Irene , Lissowska, Jolanta , Campbell, Ian G , Southey, Melissa C , Glasspool, Rosalind , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , García-Closas, Montserrat , Ekici, Arif B , Bogdanova, Natalia V , Zheng, Wei , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T
Molecular Nutrition & Food Research | July 28, 2014 | Volume: 58 | Issue: 10 | Pages: 2023-2035
ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.