Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
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Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2. / Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K; Broeks, Annegien; Van't Veer, Laura J; Hogervorst, Frans B; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Slettedahl, Seth; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Van Asperen, Christi J; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J; Hollestelle, Antoinette; van Deurzen, Carolien H M; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Pharoah, Paul D P; Dunning, Alison M; Shah, Mitul; Perkins, Barbara J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J; Meindl, Alfons; Schmutzler, Rita K; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Hunter, David J; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Easton, Douglas F; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian; GENICA Network.
in: HUM MOL GENET, Jahrgang 24, Nr. 10, 15.05.2015, S. 2966-84.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
AU - Orr, Nick
AU - Dudbridge, Frank
AU - Dryden, Nicola
AU - Maguire, Sarah
AU - Novo, Daniela
AU - Perrakis, Eleni
AU - Johnson, Nichola
AU - Ghoussaini, Maya
AU - Hopper, John L
AU - Southey, Melissa C
AU - Apicella, Carmel
AU - Stone, Jennifer
AU - Schmidt, Marjanka K
AU - Broeks, Annegien
AU - Van't Veer, Laura J
AU - Hogervorst, Frans B
AU - Fasching, Peter A
AU - Haeberle, Lothar
AU - Ekici, Arif B
AU - Beckmann, Matthias W
AU - Gibson, Lorna
AU - Aitken, Zoe
AU - Warren, Helen
AU - Sawyer, Elinor
AU - Tomlinson, Ian
AU - Kerin, Michael J
AU - Miller, Nicola
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Chistof
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Cordina-Duverger, Emilie
AU - Sanchez, Marie
AU - Bojesen, Stig E
AU - Nordestgaard, Børge G
AU - Nielsen, Sune F
AU - Flyger, Henrik
AU - Benitez, Javier
AU - Zamora, Maria Pilar
AU - Arias Perez, Jose Ignacio
AU - Menéndez, Primitiva
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Hamann, Ute
AU - Brauch, Hiltrud
AU - Justenhoven, Christina
AU - Brüning, Thomas
AU - Ko, Yon-Dschun
AU - Nevanlinna, Heli
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Khan, Sofia
AU - Bogdanova, Natalia
AU - Dörk, Thilo
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli-Matti
AU - Hartikainen, Jaana M
AU - Chenevix-Trench, Georgia
AU - Beesley, Jonathan
AU - Lambrechts, Diether
AU - Moisse, Matthieu
AU - Floris, Guiseppe
AU - Beuselinck, Benoit
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Peissel, Bernard
AU - Pensotti, Valeria
AU - Couch, Fergus J
AU - Olson, Janet E
AU - Slettedahl, Seth
AU - Vachon, Celine
AU - Giles, Graham G
AU - Milne, Roger L
AU - McLean, Catriona
AU - Haiman, Christopher A
AU - Henderson, Brian E
AU - Schumacher, Fredrick
AU - Le Marchand, Loic
AU - Simard, Jacques
AU - Goldberg, Mark S
AU - Labrèche, France
AU - Dumont, Martine
AU - Kristensen, Vessela
AU - Alnæs, Grethe Grenaker
AU - Nord, Silje
AU - Borresen-Dale, Anne-Lise
AU - Zheng, Wei
AU - Deming-Halverson, Sandra
AU - Shrubsole, Martha
AU - Long, Jirong
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Grip, Mervi
AU - Andrulis, Irene L
AU - Knight, Julia A
AU - Glendon, Gord
AU - Tchatchou, Sandrine
AU - Devilee, Peter
AU - Tollenaar, Robertus A E M
AU - Seynaeve, Caroline M
AU - Van Asperen, Christi J
AU - Garcia-Closas, Montserrat
AU - Figueroa, Jonine
AU - Chanock, Stephen J
AU - Lissowska, Jolanta
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Klevebring, Daniel
AU - Hooning, Maartje J
AU - Hollestelle, Antoinette
AU - van Deurzen, Carolien H M
AU - Kriege, Mieke
AU - Hall, Per
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Humphreys, Keith
AU - Cox, Angela
AU - Cross, Simon S
AU - Reed, Malcolm W R
AU - Pharoah, Paul D P
AU - Dunning, Alison M
AU - Shah, Mitul
AU - Perkins, Barbara J
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Ashworth, Alan
AU - Swerdlow, Anthony
AU - Jones, Michael
AU - Schoemaker, Minouk J
AU - Meindl, Alfons
AU - Schmutzler, Rita K
AU - Olswold, Curtis
AU - Slager, Susan
AU - Toland, Amanda E
AU - Yannoukakos, Drakoulis
AU - Muir, Kenneth
AU - Lophatananon, Artitaya
AU - Stewart-Brown, Sarah
AU - Siriwanarangsan, Pornthep
AU - Matsuo, Keitaro
AU - Ito, Hidema
AU - Iwata, Hiroji
AU - Ishiguro, Junko
AU - Wu, Anna H
AU - Tseng, Chiu-Chen
AU - Van Den Berg, David
AU - Stram, Daniel O
AU - Teo, Soo Hwang
AU - Yip, Cheng Har
AU - Kang, Peter
AU - Ikram, Mohammad Kamran
AU - Shu, Xiao-Ou
AU - Lu, Wei
AU - Gao, Yu-Tang
AU - Cai, Hui
AU - Kang, Daehee
AU - Choi, Ji-Yeob
AU - Park, Sue K
AU - Noh, Dong-Young
AU - Hartman, Mikael
AU - Miao, Hui
AU - Lim, Wei Yen
AU - Lee, Soo Chin
AU - Sangrajrang, Suleeporn
AU - Gaborieau, Valerie
AU - Brennan, Paul
AU - Mckay, James
AU - Wu, Pei-Ei
AU - Hou, Ming-Feng
AU - Yu, Jyh-Cherng
AU - Shen, Chen-Yang
AU - Blot, William
AU - Cai, Qiuyin
AU - Signorello, Lisa B
AU - Luccarini, Craig
AU - Bayes, Caroline
AU - Ahmed, Shahana
AU - Maranian, Mel
AU - Healey, Catherine S
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M Rosario
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C
AU - Vincent, Daniel
AU - Bacot, Francois
AU - Hunter, David J
AU - Lindstrom, Sara
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K
AU - Easton, Douglas F
AU - dos Santos Silva, Isabel
AU - Fletcher, Olivia
AU - Peto, Julian
AU - GENICA Network
AU - Harth, Volker
N1 - © The Author 2015. Published by Oxford University Press.
PY - 2015/5/15
Y1 - 2015/5/15
N2 - We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
AB - We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
U2 - 10.1093/hmg/ddv035
DO - 10.1093/hmg/ddv035
M3 - SCORING: Journal article
C2 - 25652398
VL - 24
SP - 2966
EP - 2984
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 10
ER -