Abstract
Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1680-1691 |
| Number of pages | 12 |
| Journal | Cancer Epidemiology Biomarkers and Prevention |
| Volume | 24 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2015 |
ASJC Scopus subject areas
- General Medicine
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In: Cancer Epidemiology Biomarkers and Prevention, Vol. 24, No. 11, 01.11.2015, p. 1680-1691.
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TY - JOUR
T1 - Fine-scale mapping of the 4q24 locus identifies & pr two Independent loci associated with breast cancer risk
AU - Guo, Xingyi
AU - Long, Jirong
AU - Zeng, Chenjie
AU - Michailidou, Kyriaki
AU - Ghoussaini, Maya
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Milne, Roger L.
AU - Shu, Xiao Ou
AU - Cai, Qiuyin
AU - Beesley, Jonathan
AU - Kar, Siddhartha P.
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Beckmann, Matthias W.
AU - Beeghly-Fadiel, Alicia
AU - Benitez, Javier
AU - Blot, William
AU - Bogdanova, Natalia
AU - Bojesen, Stig E.
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Brinton, Louise
AU - Broekss, Annegien
AU - Bruning, Thomas
AU - Burwinkel, Barbara
AU - Cai, Hui
AU - Canisius, Sander
AU - Chang-Claude, Jenny
AU - Choi, Ji Yeob
AU - Couch, Fergus J.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Devilee, Peter
AU - Droit, Arnaud
AU - Dork, Thilo
AU - Fasching, Peter A.
AU - Fletcher, Olivia
AU - Flyger, Henrik
AU - Fostira, Florentia
AU - Gaborieau, Valerie
AU - García-Closas, Montserrat
AU - Giles, Graham G.
AU - Grip, Mervi
AU - Guenel, Pascal
AU - Haiman, Christopher A.
AU - Hamann, Ute
AU - Hartman, Mikael
AU - Hollestelle, Antoinette
AU - Hopper, John L.
AU - Hsiung, Chia Ni
AU - Ito, Hidemi
AU - Jakubowska, Anna
AU - Johnson, Nichola
AU - Kabisch, Maria
AU - Kang, Daehee
AU - Khan, Sofia
AU - Knight, Julia A.
AU - Kosma, Veli Matti
AU - Lambrechts, Diether
AU - Le Marchand, Loic
AU - Li, Jingmei
AU - Lindblom, Annika
AU - Lophatananon, Artitaya
AU - Lubinski, Jan
AU - Mannermaa, Arto
AU - Manoukian, Siranoush
AU - Margolin, Sara
AU - Marme, Frederik
AU - Matsuo, Keitaro
AU - McLean, Catriona A.
AU - Meindl, Alfons
AU - Muir, Kenneth
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Nord, Silje
AU - Olson, Janet E.
AU - Orr, Nick
AU - Peterlongo, Paolo
AU - Putti, Thomas Choudary
AU - Rudolph, Anja
AU - Sangrajrang, Suleeporn
AU - Sawyer, Elinor J.
AU - Schmidt, Marjanka K.
AU - Schmutzler, Rita K.
AU - Shen, Chen Yang
AU - Shi, Jiajun
AU - Shrubsole, Martha J.
AU - Southey, Melissa C.
AU - Swerdlow, Anthony
AU - Teo, Soo Hwang
AU - Thienpont, Bernard
AU - Toland, Amanda Ewart
AU - Tollenaar, Robert A.E.M.
AU - Tomlinson, Ian P.M.
AU - Truong, Therese
AU - Tseng, Chiu Chen
AU - Van Den Ouweland, Ans
AU - Wen, Wanqing
AU - Winqvist, Robert
AU - Wu, Anna
AU - Yip, Cheng Har
AU - Zamora, M. Pilar
AU - Zheng, Ying
AU - Hall, Per
AU - Pharoah, Paul D.P.
AU - Simard, Jacques
AU - Chenevix-Trench, Georgia
AU - Dunning, Alison M.
AU - Easton, Douglas F.
AU - Zheng, Wei
AU - Eeles, Rosalind A.
AU - Al Olama, Ali Amin
AU - Kote-Jarai, Zsofia
AU - Benlloch, Sara
AU - Antoniou, Antonis
AU - McGuffog, Lesley
AU - Offit, Ken
AU - Lee, Andrew
AU - Dicks, Ed
AU - Luccarini, Craig
AU - Tessier, Daniel C.
AU - Bacot, Francois
AU - Vincent, Daniel
AU - La Boissière, Sylvie
AU - Robidoux, Frederic
AU - Nielsen, Sune F.
AU - Cunningham, Julie M.
AU - Windebank, Sharon A.
AU - Hilker, Christopher A.
AU - Meyer, Jeffrey
AU - Angelakos, Maggie
AU - Maskiell, Judi
AU - Van Der Schoot, Ellen
AU - Rutgers, Emiel
AU - Verhoef, Senno
AU - Hogervorst, Frans
AU - Boonyawongviroj, Prat
AU - Siriwanarungsan, Pornthep
AU - Schrauder, Michael
AU - Rübner, Matthias
AU - Oeser, Sonja
AU - Landrith, Silke
AU - Williams, Eileen
AU - Ryder-Mills, Elaine
AU - Sargus, Kara
AU - McInerney, Niall
AU - Colleran, Gabrielle
AU - Rowan, Andrew
AU - Jones, Angela
AU - Sohn, Christof
AU - Schneeweiß, Andeas
AU - Bugert, Peter
AU - Álvarez, Núria
AU - Bernstein, Leslie
AU - Lacey, James
AU - Wang, Sophia
AU - Ma, Huiyan
AU - Lu, Yani
AU - Clague De Hart, Jessica
AU - Deapen, Dennis
AU - Pinder, Rich
AU - Lee, Eunjung
AU - Schumacher, Fred
AU - Horn-Ross, Pam
AU - Reynolds, Peggy
AU - Nelson, David
AU - Park, Hannah
AU - Ziegler, Hartwig
AU - Wolf, Sonja
AU - Hermann, Volker
AU - Lo, Wing Yee
AU - Justenhoven, Christina
AU - Ko, Yon Dschun
AU - Baisch, Christian
AU - Fischer, Hans Peter
AU - Pesch, Beate
AU - Rabstein, Sylvia
AU - Lotz, Anne
AU - Harth, Volker
AU - Heikkinen, Tuomas
AU - Erkkilä, Irja
AU - Aaltonen, Kirsimari
AU - Von Smitten, Karl
AU - Antonenkova, Natalia
AU - Hillemanns, Peter
AU - Christiansen, Hans
AU - Myöhänen, Eija
AU - Kemiläinen, Helena
AU - Thorne, Heather
AU - Niedermayr, Eveline
AU - Bowtell, D.
AU - De Fazio, A.
AU - Gertig, D.
AU - Green, A.
AU - Webb, P.
AU - Green, A.
AU - Parsons, P.
AU - Hayward, N.
AU - Whiteman, D.
AU - Fung, Annie
AU - Yashiki, June
AU - Peuteman, Gilian
AU - Smeets, Dominiek
AU - Van Brussel, Thomas
AU - Corthouts, Kathleen
AU - Obi, Nadia
AU - Heinz, Judith
AU - Behrens, Sabine
AU - Eilber, Ursula
AU - Celik, Muhabbet
AU - Olchers, Til
AU - Peissel, Bernard
AU - Scuvera, Giulietta
AU - Zaffaroni, Daniela
AU - Bonanni, Bernardo
AU - Feroce, Irene
AU - Maniscalco, Angela
AU - Rossi, Alessandra
AU - Bernard, Loris
AU - Tranchant, Martine
AU - Valois, Marie France
AU - Turgeon, Annie
AU - Heguy, Lea
AU - Yee, Phuah Sze
AU - Kang, Peter
AU - Nee, Kang In
AU - Mariapun, Shivaani
AU - Sook-Yee, Yoon
AU - Lee, Daphne
AU - Ching, Teh Yew
AU - Taib, Nur Aishah Mohd
AU - Otsukka, Meeri
AU - Mononen, Kari
AU - Selander, Teresa
AU - Weerasooriya, Nayana
AU - Krol-Warmerdam, E.
AU - Molenaar, J.
AU - Blom, J.
AU - Szeszenia-Dabrowska, Neonila
AU - Peplonska, Beata
AU - Zatonski, Witold
AU - Chao, Pei
AU - Stagner, Michael
AU - Bos, Petra
AU - Crepin, Ellen
AU - Nieuwlaat, Anja
AU - Heemskerk, Annette
AU - Higham, Sue
AU - Cramp, Helen
AU - Connley, Dan
AU - Balasubramanian, Sabapathy
AU - Brock, Ian
AU - Kerin, Michael
AU - Miller, Nicola
AU - Kerbrat, Pierre
AU - Arveux, Patrick
AU - Le Scodan, Romuald
AU - Raoul, Yves
AU - Laurent-Puig, Pierre
AU - Mulot, Claire
AU - Stegmaier, Christa
AU - Butterbach, Katja
AU - Karstens, Johann H.
AU - Flesch-Janys, Dieter
AU - Seibold, Petra
AU - Vrieling, Alina
AU - Nickels, Stefan
AU - Radice, Paolo
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Kauppila, Saila
AU - Conroy, Don
AU - Baynes, Caroline
AU - Chua, Kimberley
AU - Pilarski, Robert
N1 - Publisher Copyright: © 2015 AACR.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
AB - Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
UR - http://www.scopus.com/inward/record.url?scp=84946544208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946544208&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-15-0363
DO - 10.1158/1055-9965.EPI-15-0363
M3 - Article
C2 - 26354892
AN - SCOPUS:84946544208
SN - 1055-9965
VL - 24
SP - 1680
EP - 1691
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 11
ER -