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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 P; Beesley, Jonathan; Amin Al Olama, Ali; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J and Thompson, Deborah J, et al. (2016) In Cancer Discovery 6(9). p.67-1052
Abstract

UNLABELLED: 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).... (More)

UNLABELLED: 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.

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Cancer Discovery
volume
6
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9
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16 pages
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American Association for Cancer Research
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  • wos:000383356400028
  • scopus:85012028638
ISSN
2159-8274
DOI
10.1158/2159-8290.CD-15-1227
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English
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yes
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487832de-4e6e-4ab8-8bcd-851cea227454
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2016-09-18 11:28:34
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2017-07-19 13:46:13
@article{487832de-4e6e-4ab8-8bcd-851cea227454,
  abstract     = {<p>UNLABELLED: 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 &lt; 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 &lt; 10(-5) in the three-cancer meta-analysis.</p><p>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.</p>},
  author       = {Kar, Siddhartha P and Beesley, Jonathan and Amin Al Olama, Ali and Michailidou, Kyriaki and Tyrer, Jonathan and Kote-Jarai, ZSofia and Lawrenson, Kate and Lindstrom, Sara and Ramus, Susan J and Thompson, Deborah J and Kibel, Adam S and Dansonka-Mieszkowska, Agnieszka and Michael, Agnieszka and Dieffenbach, Aida K and Gentry-Maharaj, Aleksandra and Whittemore, Alice S and Wolk, Alicja and Monteiro, Alvaro and Peixoto, Ana and Kierzek, Andrzej and Cox, Angela and Rudolph, Anja and Gonzalez-Neira, Anna and Wu, Anna H and Lindblom, Annika and Swerdlow, Anthony and Ziogas, Argyrios and Ekici, Arif B and Burwinkel, Barbara and Karlan, Beth Y and Nordestgaard, Børge G and Blomqvist, Carl and Phelan, Catherine and McLean, Catriona and Pearce, Celeste Leigh and Vachon, Celine and Cybulski, Cezary and Slavov, Chavdar and Stegmaier, Christa and Maier, Christiane and Ambrosone, Christine B and Høgdall, Claus K and Teerlink, Craig C and Kang, Daehee and Tessier, Daniel C and Schaid, Daniel J and Stram, Daniel O and Cramer, Daniel W and Neal, David E and Eccles, Diana and Flesch-Janys, Dieter and Edwards, Digna R Velez and Wokozorczyk, Dominika and Levine, Douglas A and Yannoukakos, Drakoulis and Sawyer, Elinor J and Bandera, Elisa V and Poole, Elizabeth M and Goode, Ellen L and Khusnutdinova, Elza and Høgdall, Estrid and Song, Fengju and Bruinsma, Fiona and Heitz, Florian and Modugno, Francesmary and Hamdy, Freddie C and Wiklund, Fredrik and Giles, Graham G and Olsson, Håkan and Wildiers, Hans and Ulmer, Hans-Ulrich and Pandha, Hardev and Risch, Harvey A and Darabi, Hatef and Salvesen, Helga B and Nevanlinna, Heli and Gronberg, Henrik and Brenner, Hermann and Brauch, Hiltrud and Anton-Culver, Hoda and Song, Honglin and Lim, Hui-Yi and McNeish, Iain and Campbell, Ian and Vergote, Ignace and Gronwald, Jacek and Lubiński, Jan and Stanford, Janet L and Benítez, Javier and Doherty, Jennifer A and Permuth, Jennifer B and Chang-Claude, Jenny and Donovan, Jenny L and Dennis, Joe and Schildkraut, Joellen M and Schleutker, Johanna and Hopper, John L and Kupryjanczyk, Jolanta and Park, Jong Y and Figueroa, Jonine and Clements, Judith A and Knight, Julia A and Peto, Julian and Cunningham, Julie M and Pow-Sang, Julio and Batra, Jyotsna and Czene, Kamila and Lu, Karen H and Herkommer, Kathleen and Khaw, Kay-Tee and Matsuo, Keitaro and Muir, Kenneth and Offitt, Kenneth and Chen, Kexin and Moysich, Kirsten B and Aittomäki, Kristiina and Odunsi, Kunle and Kiemeney, Lambertus A and Massuger, Leon F A G and Fitzgerald, Liesel M and Cook, Linda S and Cannon-Albright, Lisa and Hooning, Maartje J and Pike, Malcolm C and Bolla, Manjeet K and Luedeke, Manuel and Teixeira, Manuel R and Goodman, Marc T and Schmidt, Marjanka K and Riggan, Marjorie and Aly, Markus and Rossing, Mary Anne and Beckmann, Matthias W and Moisse, Matthieu and Sanderson, Maureen and Southey, Melissa C and Jones, Michael and Lush, Michael and Hildebrandt, Michelle A T and Hou, Ming-Feng and Schoemaker, Minouk J and Garcia-Closas, Montserrat and Bogdanova, Natalia and Rahman, Nazneen and Le, Nhu D and Orr, Nick and Wentzensen, Nicolas and Pashayan, Nora and Peterlongo, Paolo and Guénel, Pascal and Brennan, Paul and Paulo, Paula and Webb, Penelope M and Broberg, Per and Fasching, Peter A and Devilee, Peter and Wang, Qin and Cai, Qiuyin and Li, Qiyuan and Kaneva, Radka and Butzow, Ralf and Kopperud, Reidun Kristin and Schmutzler, Rita K and Stephenson, Robert A and MacInnis, Robert J and Hoover, Robert N and Winqvist, Robert and Ness, Roberta and Milne, Roger L and Travis, Ruth C and Benlloch, Sara and Olson, Sara H and McDonnell, Shannon K and Tworoger, Shelley S and Maia, Sofia and Berndt, Sonja and Lee, Soo Chin and Teo, Soo-Hwang and Thibodeau, Stephen N and Bojesen, Stig E and Gapstur, Susan M and Kjær, Susanne Krüger and Pejovic, Tanja and Tammela, Teuvo L J and Dörk, Thilo and Brüning, Thomas and Wahlfors, Tiina and Key, Tim J and Edwards, Todd L and Menon, Usha and Hamann, Ute and Mitev, Vanio and Kosma, Veli-Matti and Setiawan, Veronica Wendy and Kristensen, Vessela and Arndt, Volker and Vogel, Walther and Zheng, Wei and Sieh, Weiva and Blot, William J and Kluzniak, Wojciech and Shu, Xiao-Ou and Gao, Yu-Tang and Schumacher, Fredrick and Freedman, Matthew L and Berchuck, Andrew and Dunning, Alison M and Simard, Jacques and Haiman, Christopher A and Spurdle, Amanda and Sellers, Thomas A and Hunter, David J and Henderson, Brian E and Kraft, Peter and Chanock, Stephen J and Couch, Fergus J and Hall, Per and Gayther, Simon A and Easton, Douglas F and Chenevix-Trench, Georgia and Eeles, Rosalind and Pharoah, Paul D P and Lambrechts, Diether and , },
  issn         = {2159-8274},
  language     = {eng},
  number       = {9},
  pages        = {67--1052},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Discovery},
  title        = {Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types},
  url          = {http://dx.doi.org/10.1158/2159-8290.CD-15-1227},
  volume       = {6},
  year         = {2016},
}