Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. / Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Kuchenbaecker, Karoline B; Droit, Arnaud; Michailidou, Kyriaki; Ghoussaini, Maya; Kar, Siddhartha; Freeman, Adam; Hopper, John L; Milne, Roger L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Agata, Simona; Ahmed, Shahana; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arason, Adalgeir; Arndt, Volker; Arun, Banu K; Arver, Brita; Bacot, Francois; Barrowdale, Daniel; Baynes, Caroline; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Blot, William J; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Carpenter, Jane; Chang-Claude, Jenny; Choi, Ji-Yeob; Claes, Kathleen B M; Clarke, Christine; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; de la Hoya, Miguel; De Leeneer, Kim; Devilee, Peter; Diez, Orland; Domchek, Susan M; Doody, Michele; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Dwek, Miriam; Dworniczak, Bernd; Egan, Kathleen; Eilber, Ursula; Einbeigi, Zakaria; Ejlertsen, Bent; Ellis, Steve; Frost, Debra; Lalloo, Fiona; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Friedlander, Michael; Friedman, Eitan; Gambino, Gaetana; Gao, Yu-Tang; Garber, Judy; García-Closas, Montserrat; Gehrig, Andrea; Damiola, Francesca; Lesueur, Fabienne; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Giles, Graham G; Godwin, Andrew K; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hartikainen, Jaana M; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Hogervorst, Frans B L; Verhoef, Senno; Hendricks, Carolyn B; Hillemanns, Peter; Hollestelle, Antoinette; Hulick, Peter J; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Joly Beauparlant, Charles; Jones, Michael; Kabisch, Maria; Kang, Daehee; Karlan, Beth Y; Kauppila, Saila; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Knight, Julia A; Konstantopoulou, Irene; Kraft, Peter; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Le Marchand, Loic; Lee, Chuen Neng; Lee, Min Hyuk; Lester, Jenny; Li, Jingmei; Liljegren, Annelie; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mai, Phuong L; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McGuffog, Lesley; Meindl, Alfons; Menegaux, Florence; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Newcomb, Polly A; Nord, Silje; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olswold, Curtis; Osorio, Ana; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Peeters, Stephanie; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Presneau, Nadege; Radice, Paolo; Rahman, Nazneen; Ramus, Susan J; Rashid, Muhammad Usman; Rennert, Gad; Rhiem, Kerstin; Salani, Ritu; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schoemaker, Minouk J; Schürmann, Peter; Seynaeve, Caroline; Shen, Chen-Yang; Shrubsole, Martha J; Shu, Xiao-Ou; Sigurdson, Alice; Singer, Christian F; Slager, Susan; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Swerdlow, Anthony; Szabo, Csilla I; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Mary Beth; Tessier, Daniel C; Teulé, Alex; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tung, Nadine; Turnbull, Clare; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Ven den Berg, David; Vijai, Joseph; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Whittemore, Alice S; Winqvist, Robert; Wong, Tien Y; Wu, Anna H; Yannoukakos, Drakoulis; Yu, Jyh-Cherng; Pharoah, Paul D P; Hall, Per; Chenevix-Trench, Georgia; Dunning, Alison M; Simard, Jacques; Couch, Fergus J; Antoniou, Antonis C; Easton, Douglas F; Zheng, Wei; EMBRACE.
in: BREAST CANCER RES, Jahrgang 18, Nr. 1, 21.06.2016, S. 64.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
AU - Zeng, Chenjie
AU - Guo, Xingyi
AU - Long, Jirong
AU - Kuchenbaecker, Karoline B
AU - Droit, Arnaud
AU - Michailidou, Kyriaki
AU - Ghoussaini, Maya
AU - Kar, Siddhartha
AU - Freeman, Adam
AU - Hopper, John L
AU - Milne, Roger L
AU - Bolla, Manjeet K
AU - Wang, Qin
AU - Dennis, Joe
AU - Agata, Simona
AU - Ahmed, Shahana
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia N
AU - Arason, Adalgeir
AU - Arndt, Volker
AU - Arun, Banu K
AU - Arver, Brita
AU - Bacot, Francois
AU - Barrowdale, Daniel
AU - Baynes, Caroline
AU - Beeghly-Fadiel, Alicia
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Blomqvist, Carl
AU - Blot, William J
AU - Bogdanova, Natalia V
AU - Bojesen, Stig E
AU - Bonanni, Bernardo
AU - Borresen-Dale, Anne-Lise
AU - Brauch, Hiltrud
AU - Brennan, Paul
AU - Brenner, Hermann
AU - Broeks, Annegien
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Buys, Saundra S
AU - Cai, Qiuyin
AU - Caldes, Trinidad
AU - Campbell, Ian
AU - Carpenter, Jane
AU - Chang-Claude, Jenny
AU - Choi, Ji-Yeob
AU - Claes, Kathleen B M
AU - Clarke, Christine
AU - Cox, Angela
AU - Cross, Simon S
AU - Czene, Kamila
AU - Daly, Mary B
AU - de la Hoya, Miguel
AU - De Leeneer, Kim
AU - Devilee, Peter
AU - Diez, Orland
AU - Domchek, Susan M
AU - Doody, Michele
AU - Dorfling, Cecilia M
AU - Dörk, Thilo
AU - Dos-Santos-Silva, Isabel
AU - Dumont, Martine
AU - Dwek, Miriam
AU - Dworniczak, Bernd
AU - Egan, Kathleen
AU - Eilber, Ursula
AU - Einbeigi, Zakaria
AU - Ejlertsen, Bent
AU - Ellis, Steve
AU - Frost, Debra
AU - Lalloo, Fiona
AU - Fasching, Peter A
AU - Figueroa, Jonine
AU - Flyger, Henrik
AU - Friedlander, Michael
AU - Friedman, Eitan
AU - Gambino, Gaetana
AU - Gao, Yu-Tang
AU - Garber, Judy
AU - García-Closas, Montserrat
AU - Gehrig, Andrea
AU - Damiola, Francesca
AU - Lesueur, Fabienne
AU - Mazoyer, Sylvie
AU - Stoppa-Lyonnet, Dominique
AU - Giles, Graham G
AU - Godwin, Andrew K
AU - Goldgar, David E
AU - González-Neira, Anna
AU - Greene, Mark H
AU - Guénel, Pascal
AU - Haeberle, Lothar
AU - Haiman, Christopher A
AU - Hallberg, Emily
AU - Hamann, Ute
AU - Hansen, Thomas V O
AU - Hart, Steven
AU - Hartikainen, Jaana M
AU - Hartman, Mikael
AU - Hassan, Norhashimah
AU - Healey, Sue
AU - Hogervorst, Frans B L
AU - Verhoef, Senno
AU - Hendricks, Carolyn B
AU - Hillemanns, Peter
AU - Hollestelle, Antoinette
AU - Hulick, Peter J
AU - Hunter, David J
AU - Imyanitov, Evgeny N
AU - Isaacs, Claudine
AU - Ito, Hidemi
AU - Jakubowska, Anna
AU - Janavicius, Ramunas
AU - Jaworska-Bieniek, Katarzyna
AU - Jensen, Uffe Birk
AU - John, Esther M
AU - Joly Beauparlant, Charles
AU - Jones, Michael
AU - Kabisch, Maria
AU - Kang, Daehee
AU - Karlan, Beth Y
AU - Kauppila, Saila
AU - Kerin, Michael J
AU - Khan, Sofia
AU - Khusnutdinova, Elza
AU - Knight, Julia A
AU - Konstantopoulou, Irene
AU - Kraft, Peter
AU - Kwong, Ava
AU - Laitman, Yael
AU - Lambrechts, Diether
AU - Lazaro, Conxi
AU - Le Marchand, Loic
AU - Lee, Chuen Neng
AU - Lee, Min Hyuk
AU - Lester, Jenny
AU - Li, Jingmei
AU - Liljegren, Annelie
AU - Lindblom, Annika
AU - Lophatananon, Artitaya
AU - Lubinski, Jan
AU - Mai, Phuong L
AU - Mannermaa, Arto
AU - Manoukian, Siranoush
AU - Margolin, Sara
AU - Marme, Frederik
AU - Matsuo, Keitaro
AU - McGuffog, Lesley
AU - Meindl, Alfons
AU - Menegaux, Florence
AU - Montagna, Marco
AU - Muir, Kenneth
AU - Mulligan, Anna Marie
AU - Nathanson, Katherine L
AU - Neuhausen, Susan L
AU - Nevanlinna, Heli
AU - Newcomb, Polly A
AU - Nord, Silje
AU - Nussbaum, Robert L
AU - Offit, Kenneth
AU - Olah, Edith
AU - Olopade, Olufunmilayo I
AU - Olswold, Curtis
AU - Osorio, Ana
AU - Papi, Laura
AU - Park-Simon, Tjoung-Won
AU - Paulsson-Karlsson, Ylva
AU - Peeters, Stephanie
AU - Peissel, Bernard
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Pfeiler, Georg
AU - Phelan, Catherine M
AU - Presneau, Nadege
AU - Radice, Paolo
AU - Rahman, Nazneen
AU - Ramus, Susan J
AU - Rashid, Muhammad Usman
AU - Rennert, Gad
AU - Rhiem, Kerstin
AU - Salani, Ritu
AU - Sangrajrang, Suleeporn
AU - Sawyer, Elinor J
AU - Schmidt, Marjanka K
AU - Schmutzler, Rita K
AU - Schoemaker, Minouk J
AU - Schürmann, Peter
AU - Seynaeve, Caroline
AU - Shen, Chen-Yang
AU - Shrubsole, Martha J
AU - Shu, Xiao-Ou
AU - Sigurdson, Alice
AU - Singer, Christian F
AU - Slager, Susan
AU - Soucy, Penny
AU - Southey, Melissa
AU - Steinemann, Doris
AU - Swerdlow, Anthony
AU - Szabo, Csilla I
AU - Tchatchou, Sandrine
AU - Teixeira, Manuel R
AU - Teo, Soo H
AU - Terry, Mary Beth
AU - Tessier, Daniel C
AU - Teulé, Alex
AU - Thomassen, Mads
AU - Tihomirova, Laima
AU - Tischkowitz, Marc
AU - Toland, Amanda E
AU - Tung, Nadine
AU - Turnbull, Clare
AU - van den Ouweland, Ans M W
AU - van Rensburg, Elizabeth J
AU - Ven den Berg, David
AU - Vijai, Joseph
AU - Wang-Gohrke, Shan
AU - Weitzel, Jeffrey N
AU - Whittemore, Alice S
AU - Winqvist, Robert
AU - Wong, Tien Y
AU - Wu, Anna H
AU - Yannoukakos, Drakoulis
AU - Yu, Jyh-Cherng
AU - Pharoah, Paul D P
AU - Hall, Per
AU - Chenevix-Trench, Georgia
AU - Dunning, Alison M
AU - Simard, Jacques
AU - Couch, Fergus J
AU - Antoniou, Antonis C
AU - Easton, Douglas F
AU - Zheng, Wei
AU - EMBRACE Collaborators
PY - 2016/6/21
Y1 - 2016/6/21
N2 - BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
AB - BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
U2 - 10.1186/s13058-016-0718-0
DO - 10.1186/s13058-016-0718-0
M3 - SCORING: Journal article
C2 - 27459855
VL - 18
SP - 64
JO - BREAST CANCER RES
JF - BREAST CANCER RES
SN - 1465-5411
IS - 1
ER -
